1 An Update on the Biomedical Prospects of Marine-derived ...€¦ · drug discovery, wherein they...

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1 An Update on the BiomedicalProspects of Marine-derived SmallMolecules with Fascinating Atom andStereochemical Diversity

Yvette Mimieux Vaske and Phillip CrewsDepartment of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA

1.1 INTRODUCTION

In this chapter we discuss a selection of structurally diverse marine-derived small molecules (MDSMs)with potent and/or specific bioactivity and analyze their biomedical applications. The compoundsincluded have been isolated either from marine macroorganisms, including sponges, ascidians (tuni-cates), bryozoans, and molluscs, or from microorganisms, such as bacteria and fungi. Our inquirybegins with a look back in time at a selection of important marine natural products, with particularfocus on compounds in the clinical pipeline. The chapter continues with an analysis of a biosynthet-ically diverse assortment of 22 MDSMs and their structural elements of atom and stereochemicaldiversity. Entries have been divided into five biosynthetic classes: terpene, polyketide, alkaloid, dep-sipeptide, and polyketide–peptide. Enormous structural variety is represented by the marine naturalproducts treated herein. The compounds selected can be considered to represent case examples of sig-nificant biomolecules with positivity and, in some cases, potent bioactivity accompanied by an unusualmechanism of action.

1.1.1 Overview of known compounds, highlightingmolecules of significance

The ocean covers more than 70% of the earth’s surface and is home to exceptional biodiversity:more than one million marine species and an estimated one billion different kinds of marine microbe(Census of Marine Life Press Release 2010). We and others firmly believe that MDSMs represent acontinuing resource for tools important in cell biology research and in the design of the next-generationleads for drug discovery and development. The record to date firmly illustrates that the structures ofnatural products continue to be invaluable in expanding pharmacophore structural space. For example,Newman and Cragg recently provided a detailed analysis of the last 30 years of natural products indrug discovery, wherein they contended that, “Nature’s ‘treasure trove of small molecules’ remains tobe explored, particularly from the marine and microbial environments” (Newman & Cragg 2012).

Bioactive Compounds from Marine Foods: Plant and Animal Sources, First Edition.Edited by Blanca Hernandez-Ledesma and Miguel Herrero.© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

COPYRIG

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ATERIAL


2 Bioactive Compounds from Marine Foods

It is appropriate to return to a theme expressed in the past based on ecology and natural history. Sim-ply stated, marine-derived biosynthetic products must have unprecedented chemodiversity (NationalResearch Council 2002) in comparison to those from the terrestrial realm, due to the difference inbiosynthetic machinery that must exist between the macroorganisms abundant in these different envi-ronments. The structures shown in this review will provide the reader with up-to-date informationrelated to these results. On the horizon is the demonstration that stunning natural products will bediscovered from marine-derived strains isolated and re-cultured grown under saline conditions (Imhoffet al. 2011). Thus, many of the molecules discussed in this chapter have been chosen to illustrate theheadway being made in this direction.

This treatise extends to recent annual reviews in the literature, which focus on several importantissues. At the top of the list are discussions of marine natural products in biomedical investigations, andthere is a steady stream of such comprehensive papers (Hughes & Fenical 2010a; Radjasa et al. 2011;Gerwick & Moore 2012). The dynamic pipeline of MDSMs into “marine pharmaceuticals” has beenwell documented by reviews in the peer-reviewed literature (Newman & Cragg 2004, 2012; Fenical2006; Molinski et al. 2009; Mayer et al. 2010; Montaser & Luesch 2011). It is also important to beaware of accounts of marine natural products structural revisions (Suyama et al. 2011). Central toefforts to confirm structure assignment and absolute stereochemistry has been the interplay betweentotal syntheses and reexamination of the spectroscopic data (Suyama et al. 2011). Lastly, a furtherindication of the importance of MDSMs in biomedical discovery is a recent in-depth review dedicatedto aspects surrounding the organic synthesis of biologically active marine natural products (Morris &Phillips 2011).

1.1.1.1 Clinical candidates and MDSM chemical probesMarine macro- and microorganisms are sources of tremendous chemodiversity and offer new scaffoldsfor biomedical exploration. The connection between an MDSM’s structure, biological activity, andbiological target for mechanism of action is at the crux of collaborative investigations by the marinenatural products, synthetic, and chemical biology communities. Illustrated in Figure 1.1 is a selectionof four important marine-derived natural products which summarize those molecules that are (a)presently used as synthetic clinical therapeutics and (b) employed as chemical probes in chemicalbiology, biochemistry, and molecular genetics to further our understanding of biological function.The biosynthetic classes, biological targets, and commercial sources, if available, are given below thestructures, as is additional citation information useful in further current-awareness searches.

There are two complex structures in Figure 1.1, either of which can be considered a poster child forexotic yet exceedingly important scaffolds. Both possess a blizzard of chiral centers and a density offunctionalization. But the pathways to their respective developments as preclinical or clinical agentswere slightly different. The former possesses a virtually identical synthetic scaffold to the naturalproduct. Here is a brief outline. Irvalec® (panel A1), under development by PharmaMar (Spain;www.pharmamar.com), is an unnatural salt of isokahalalide F, a natural product congener co-isolatedwith kahalalide F (11 in Figure 1.2) (Gao et al. 2009). Alternatively, eribulin mesylate (E7389)represents a reduced-complexity analogue of a very complex natural product. This compound ismarketed as Halaven® (Eisai, Japan; www.eisai.com) and gained US Food and Drug Administration(FDA) approval in November 2010 for treatment of metastatic breast cancer unresponsive to other drugtreatments (Jefferson 2010). A combined synthetic—structure–activity relationship (SAR) investigationfound that the entire western portion of halichondrin B (2) could be truncated without a deleteriouseffect on the therapeutic activity (Qi & Ma 2011).

Two additional compounds are shown in Figure 1.1b, which represent commercially availableMDSM chemical probes. We have adopted the definition of a “chemical probe” set forth in an editorial inNature Chemical Biology (Editorial 2010) and elaborated on in a commentary by Frye (2010): “Potent,selective and cell-permeable small molecules that perturb a biological target in a dose-dependentmanner [and] can be used to dynamically ‘probe’ the role of the target in biology.” Terrestrial andmarine natural-product chemical probes were recently reviewed by Carlson (2010), and the reader is


An Update on the Biomedical Prospects 3

(a)

(b)

Figure 1.1 A snapshot of marine-derived natural products highlighting (a) clinical therapeutics (Irvalec®(Elisidepsin, PM02734) and Halaven® (Eribulin mesylate, E7389)) and (b) chemical probes (Jasplakinolideand Psammaplin A).

encouraged to refer to the literature for additional perspective. The notion that natural products haveevolved for specificity towards biological macromolecules, particularly proteins and genes, is supportedby the community (Clardy & Walsh 2004; Piggott & Karuso 2004; Carlson 2010). The sponge-derived probes jasplakinolide and psammaplin A are both important MDSM chemical probes and thereader is directed to recent literature surrounding their biological function (Boulant et al. 2011; Baudet al. 2012).

1.1.2 Selected important marine sources of MDSMsThe annual review “Marine Natural Products” by Blunt et al. (2005, 2006, 2007, 2008, 2010, 2011,2012) in Natural Products Reports (NPR) provides a detailed perspective on the publication record



Figure 1.2 A glimpse into the past via a selection of 14 invertebrate- and microorganism-derived naturalproducts in clinical use or of therapeutic potential.



1100(a)

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Figure 1.3 A recent snapshot of MDSMs in the literature, highlighting (a) a histogram of the numberof compounds reported between 2003 and 2010, and (b) an expanded view of MDSM sources reportedbetween 2008 and 2010. (Adapted from Blunt et al. 2005, 2006; 2007, 2008, 2010, 2011, 2012).∗Microorganisms: fungi, bacteria, phytoplankton, and brown, green, and red algae. (For a color versionof this figure, please see the color plate section.)

of peer-reviewed compounds, with an emphasis on new compounds and their biological activities.Marine natural products are also entered and tabulated in MarinLit, a database of the marine nat-ural products literature produced and maintained by the Department of Chemistry, University ofCanterbury, New Zealand (http://www.chem.canterbury.ac.nz/marinlit/marinlit.shtml). Figure 1.3a is ahistogram of the number of marine natural products reported in the literature between 2003 and 2010.It shows an upward trend, with the number of new compounds reported annually increasing for theyears examined.

Marine natural products included in the annual NPR review consist of published MDSMs isolatedfrom both macroorganisms, such as sponges, cnidarians, bryozoans, molluscs, tunicates, and echin-oderms, and microorganisms, such as fungi, bacteria, phytoplankton, green algae, brown algae, andred algae. Figure 1.3b shows an expanded view of MDSMs reported in the literature between 2008and 2010 by Blunt et al. (2010, 2011, 2012). The approximate percentages are as follows: sponges,31.9%; microorganisms, 30.7%; cnidarians, 24.7%; tunicates (ascidians), 4.3%; bryozoans, 0.8%. It isinteresting to note that the three top producers of marine natural products are sponges, microorgan-isms, and cnidarians. Consistently, the majority of the MDSMs in this chapter are from sponge andmicroorganism (fungus and bacterium) sources.



1.1.2.1 Macroorganisms: an analysis of their critical roleThe marine invertebrate groups of interest in the isolation of MDSMs include phyla such as Porifera,Coelenterata, Mollusca, Tunicata, and Annelida. A recent analysis by Leal et al. (2012) examined newMDSMs from invertebrates that appeared over the last 20 years. Marine macroorganisms are valuableproducers of biomedically relevant MDSMs, many of which serve as therapeutic lead compounds, suchthat future conservation efforts are imperative in preserving marine invertebrates and the bionetworksthat support them (Kingston 2011). Reef-invertebrate marine natural products have previously beenreviewed in the literature, and the reader is directed to other references for further discussion andperspective (Fenical 2006; Carrol & Crews 2010; Mayer et al. 2010; Radjasa et al. 2011).

1.1.2.2 Microorganisms: questions about their being the actual sourceMarine microorganisms are increasingly the focus of marine natural products isolation efforts, as theyhave proven to be prolific producers of chemodiverse MDSMs (Zhu et al. 2011). The advancementof biomolecular technology, particularly genomic and metagenomic techniques and analysis, offersthe advantage of allowing sustainable investigation of MDSMs from renewable sources (Imhoff et al.2011). Representative groups from the kingdoms Fungi and Bacteria will be considered in this chapter(Gerwick & Moore 2012; Zotchev 2012). Advancements in seawater isolation and fermentation tech-niques have facilitated investigation of marine-derived fungal and bacterial strains and have led to theisolation of novel secondary metabolites (Radjasa et al. 2011).

1.1.3 Highlights of MDSMs of therapeutic potentialTable 1.1 and Figure 1.2 present 14 examples of MDSMs in clinical use or of therapeutic potential, mostof which have been the subjects of extensive reviews (Mayer et al. 2010; Montaser & Luesch 2011;Radjasa et al. 2011; Gerwick & Moore 2012; Newman & Cragg 2012). The compounds in Table 1.1illustrate the chemodiversity of secondary metabolites from marine invertebrate and microorganismsources. Ecteinascidin 743 (4), commercially known as Yondelis® (PharmaMar), from an ascidian(EU approved 2007), and ziconotide (14), whose commercial name is Prialt® (Elan Corp., Ireland;www.elan.com), from a cone shell (US approved 2004), are two flagship, clinically used compoundsbased precisely on a marine natural product (Radjasa et al. 2011). For many of the MDSMs in Table1.1, the supply problem has been addressed by either total synthesis of the MDSM or synthetic redesignof a simplified analogue. The table also includes comments providing further points of reference.

1.1.3.1 TerpeneThe diterpene–glycoside pseudopterosin (1) is a significant potent antiinflammatory agent and the basisof the Estee Lauder cosmetic cream Resilience (Kerr 2000). Additional analogues of this compoundhave been evaluated as wound-healing agents (Haimes & Jimenez 1997; Hoarau et al. 2008). Discoveredin the 1980s, it still represents a landmark and useful development; its privileged chemical structurecontinues to inspire many researchers.

1.1.3.2 PolyketideAn exceedingly important entry here is represented by the structure of sponge-derived halichondrinB (2). After decades of study, a monumental synthesis campaign uncovered a reduced complexitysubstructure with exquisite antitumor activity. As already noted, the clinically approved analogue,derived by total synthesis, is eribulin mesylate, E7389 (Halaven®) (Figure 1.1a). A second example inthis biosynthetic class is fijianolide B (3) (laulimalide), a cytotoxic agent with microtubule stabilizingactivity similar to that of paclitaxel (Qi & Ma 2011).



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1.1.3.3 AlkaloidThe tunicate compound ecteinascidin 743 (4), also known as ET-743, trabectedin, and marketedas Yondelis® (PharmaMar), was the first clinically approved chemotherapeutic “based on an actualmarine natural product” (Carrol & Crews 2010). This compound is currently used in the EU to treatrhabdomyosarcoma and platinum-sensitive ovarian cancers (Radjasa et al. 2011). Due to the lowisolated yield of 4, the clinically used material was obtained by kilogram semisynthesis (Tsuji 1985;Cuevas et al. 2000; Cuevas & Francesch 2009).

Microbes and/or microbial associations offer the promise of a renewable and sustainable source ofsignificant MDSMs, especially as new culturing strategies emerge (Radjasa et al. 2011). An encour-aging example is given by manzamine A (5), which has reportedly been produced by the cultureof Micromonsopora M42 (Peraud 2006). A second remarkable example is the proteosome-inhibitorsalinosporamide A (6) (NPI-0052) (marizomib), which was isolated from a salt obligate actinomycete,Salinispora tropica, presently under phase I clinical investigation for anticancer therapeutic develop-ment by Nereus Pharmaceuticals (USA; www.nereuspharm.com) (Fenical et al. 2009).

Organic synthesis has reliably resolved this resupply problem, providing entry to material for clinicalevaluation. The mollusc Jorunna funebris-derived alkaloid jorumycin (7) served as the scaffold for thesynthetic compound Zalypsis® (PharmaMar), an anticancer agent presently in phase II cancer clinicaltrials (Mayer et al. 2010). (−)-phenylahistin (8) (halimide) (NPI-2350) is the MDSM structural basisof the synthetic clinical candidate plinabulin (NPI-2358) (Nereus Pharm.) (Mita et al. 2010).

1.1.3.4 DepsipeptideThe potent antiproliferative didemnin B (9) was the first marine natural product to be investigated inphase I human cancer clinical trials; despite later being dropped, this was a milestone for MDSMs.Dehydrodidemnin B, aplidine (10), is a redesigned analogue replacing didemnin B and is presentlyunder development by PharmaMar and marketed as Aplidin® (Lee et al. 2012). Phase III cancer trialsof 10 in combination therapy for multiple myeloma are underway at this time, with organic synthesisaffording the clinical material (ClinicalTrials.gov 2012; Lee et al. 2012). Aplidin® is presently in clinicaluse in the EU (EU approved 2003) under an orphan drug status as a therapy for acute lymphoblasticleukemia. As previously alluded to, the mollusc Elysia rufescens kahalalide F (11) is the structuralscaffold of the clinically used synthetic anticancer agent Irvalec® (PharmaMar) (Figure 1.1a).

1.1.3.5 Polyketide–peptideThe marine macrolide latrunculin (12) is an important chemical probe whose biological target is actininhibition (Radjasa et al. 2011). A further discussion of the identification of the biological targets of 12will be presented in Section 1.4. An example of a linear peptide is given by the lipophilic marine fungalmetabolite halovir A (13), from Scytalidium strain CNL240 (Rowley et al. 2003). This peptide is apotent in vitro inhibitor of herpes simplex viruses 1 and 2 and was the subject of a coupled synthesis–SAR investigation in which the pharmacophore was identified for optimal therapeutic activity (Rowleyet al. 2004).

The polypeptide snail-derived toxin ziconotide (14), also known as �-conotoxin, MVIIA, SNX-111,or ziconotide acetate, marketed as Prialt®, is another striking example of a marine-derived drug thathas successfully overcome the resupply challenge (Radjasa et al. 2011). Clinically used as an analgesicin both the USA (Elan Corporation) and the EU (Eisai), Prialt® is obtained by synthesis to afford adrug identical to the snail toxin (Mayer et al. 2010).

1.1.4 New insights and lessons that addresssupply challenges

The collection of MDSMs in Table 1.1 and Figure 1.2 provides illustrative examples of various strategiesemployed by researchers to overcome the resupply challenges in the development of MDSM-inspired



clinical therapeutics (Radjasa et al. 2011). Another compelling example of a similar achievementis given by the recent disclosure by Xu et al. (2012) of an elegant investigation of didemnin B (9)biosynthesis. Throughout the preclinical and early clinical development of the antiproliferative 9, thelow isolation yield of the ascidian–MDSM posed a significant challenge. A similar resupply challengewas encountered in the development of analogue 10. Remarkably, Xu et al. (2012) identified didemninsas bacterial secondary metabolites of �-proteobacterial Tistrella mobilis and Tistrella bauzanenis. Viathe complete genome sequence and annotation of T. mobilis strain, two significant findings wereachieved: (1) identification of the putative biosynthetic didemnin (did) cluster, and (2) identification ofa post-synthetase maturation process in the biosynthesis of didemnin B. This extraordinary contributionwill undoubtedly pave the way for future genetic bioengineering studies and provide access to didemninanalogues, both of which will function as an enduring solution to the resupply challenge.

1.2 A VIEW BASED ON ATOM DIVERSITY

Eleven structures are presented in Table 1.2 and Figure 1.4 to illustrate the outstanding atom diversityof MDSMs, compiled according to biosynthetic classes. The MDSMs included in Table 1.2 are derivedfrom three of the most prolific groups: sponges, fungi, and bacteria. The marine natural products inthis section represent tremendous chemical diversity and highlight the biosynthetic richness withinthe different structural classes. Each product’s molecular formula and unsaturation number (UN) aregiven as a measure of atom diversity, and comments are provided to direct the reader to additionalinformation.

1.2.1 TerpeneAlotaketal A (15), isolated from the marine sponge Hamigera sp., collected in Papua New Guinea,is an unusual sesterterpenoid, having a molecular formula of C25H34O4 and nine sites of unsaturation(Forestieri et al. 2009). Sponge–metabolite 15 has two unusual structural features of note: (1) anunprecedented spiroketal substructure and (2) an appended monocyclic regular sesterterpenoid carbonskeleton. Equally impressive is that 15 is a potent agonist of second messenger cAMP cell-signalingpathway, with a half-maximal effective concentration (EC50) of 18 nM, at which it increases intracellularcAMP levels 170 times more effectively than the commercially available chemical probe forskolin(EC50 = 3 �M) (Forestieri et al. 2009). Support for the biomedical promise of 15 comes in the form ofthe recent enantioselective total synthesis of the MDSM 15 (Huang et al. 2012). Chemical probes havealso been employed to evaluate the agonistic cAMP signaling of 15, in order to facilitate SAR studies.

1.2.2 PolyketideSponge-derived enigmazole A (16) is a novel phosphate polyketide–alkaloid isolated from Cinachyrellaenigmatica, a Papua New Guinea marine sponge (Oku et al. 2010). Enigmazole A has the molecularformula C29H46NO10P and nine sites of unsaturation, at which the phosphate functionality is unprece-dented in marine macrolides. It is an excellent example of significant atom diversity. Inspection of16 reveals extensive methylation and hydroxylation, both of which provide support for polyketidebiosynthesis, whereas the appended oxazole moiety is the result of alkaloid biosynthesis (Oku et al.2010). The phosphomacrolide 16 displays impressive cytotoxicity in the National Cancer Institute(NCI) 60-cell-line screen, yielding a required concentration to achieve 50% growth inhibition (GI50)average of 1.7 �M however, 16 lacks tumor cell selectivity. Further, sponge–metabolite 16 displayspromising inhibitory activity against the receptor tyrosine kinase proto-oncogene c-Kit, whereby muta-tions of this molecular target are implicated in certain cancers (Lennartson & Ronnstrand 2006). Theenantioselective total synthesis of 16 was reported in a back-to-back isolation–synthesis disclosure inthe same issue (June 2010) and was achieved in 22 steps with an overall 0.41% yield (Skepper et al.2010), providing a route to 16 for further biomedical investigation.



Table

1.2

Ase

lect

ion

of11

mar

ine-

deriv

edna

tura

lpro

duct

s,ill

ustra

ting

inte

resti

ngat

oman

d/or

func

tiona

lgro

updi

vers

ity.

Entr

yN

atu

ralp

roduct

Org

anis

mso

urc

eBio

synth

etic

class

Mole

cula

rfo

rmula

UN

Com

men

ts

1A

lota

keta

lA(1

5)

Sponge

Ham

iger

asp

.Se

sterte

rpen

oid

C25

H34

O4

9Fa

scin

atin

gsp

iroyc

yclic

fram

ewor

k.Po

tent

agon

isto

fcA

MP

cell-

sign

alin

gpa

thw

ay.

2En

igm

azol

eA

(16

)Sp

onge

Cin

achy

rella

enig

mat

ica

Phos

phat

epo

lyke

tide–

alka

loid

C29

H46

NO

10P

9Fi

rstm

arin

e-de

rived

phos

phom

acro

lide

from

am

arin

eso

urce

.Stru

ctur

eco

nfirm

edby

tota

lsy

nthe

sis.

3Za

mam

idin

eA

(17

)Sp

onge

Am

phim

edon

sp.

Alk

aloi

dC

49H

60N

6O

23In

vitro

cyto

toxi

city

agai

nstP

388

mur

ine

leuk

emia

.4

Neo

petro

siam

ine

A(1

8)

Sponge

Neo

petro

sia

prox

ima .

Alk

aloi

dC

30H

52N

26

Invi

troin

hibi

tion

agai

nst

Myc

obac

teriu

mtu

berc

ulos

isan

dPl

asm

odiu

mfa

lcip

arum

,with

out

sign

ifica

ntcy

ctot

oxic

ity.

5Sp

leno

cin

A(1

9)

Bact

eriu

mSt

rept

omyc

essp

.A

lkal

oid

C26

H28

N2O

914

Pote

ntin

hibi

toro

fpro

-infla

mm

ator

ycy

toki

nepr

oduc

tion

insp

leno

cyte

cyto

kine

assa

y;an

tiasth

ma

activ

ity.

6Pl

ecto

spha

eroi

cA

cid

A(2

0)

Fungus

Plec

tosp

haer

ella

cucu

mer

ina

Alk

aloi

d–di

keto

pipe

rzin

eC

39H

32N

6O

10S 2

27In

vitro

inhi

bitio

nof

indo

leam

ine

2,3-

diox

ygen

ase

(IDO

).

7( E

,Z)-b

asta

din

19(2

1)

Sponge

Iant

hella

cf.re

ticul

ata

Brom

inat

ed–a

lkal

oid

C34

H27

Br5N

4O

821

Firs

trep

orto

fbas

tadi

ncl

ass

( Z)-o

xim

oam

ide

confi

gura

tion.

8A

mm

osam

ide

A(2

2)

Bact

eriu

mSt

rept

omyc

essp

.C

hlor

inat

ed-a

lkal

oid

C12

H10

ClN

5O

S10

Aw

esom

estr

uctu

ralc

halle

nge:

core

ratio

H/C

�1.

X-ra

yda

taan

alys

isus

edto

solv

estr

uctu

re.

9La

rgaz

ole

(23

)Cyanobact

eriu

mSy

mpl

oca

sp.

Dep

sipe

ptid

eC

29H

42N

4O

5S 3

11N

anom

olar

antip

rolif

erat

ive

activ

ityid

entifi

edas

histo

nede

acet

ylas

ein

hibi

tor.

10C

arm

aphy

cin

A(2

4)

Cyanobact

eriu

mSy

mpl

oca

sp.

Pept

ide

C25

H45

N3O

6S

5C

ytot

oxic

and

cyto

static

thro

ugh

inhi

bitio

nof

the

20S

prot

easo

me.

11Bi

sebr

omoa

mid

e(2

5)

Cyanobact

eriu

mLy

ngby

asp

.Br

omin

ated

-pep

tide

C51

H72

BrN

7O

8S

19Pr

otei

nki

nase

inhi

bito

rand

actin

filam

ents

tabi

lizer

.Stru

ctur

ere

vise

dfo

llow

ing

tota

lsyn

thes

is.

UN

,uns

atur

atio

nnu

mbe

r.



Figure 1.4 A selection of 11 marine-derived natural products, illustrating interesting atom and/or func-tional group diversity.

1.2.3 AlkaloidGiven the molecular formula of C49H60N6O, the manzamine alkaloid zamamidine A (17) has 23sites of unsaturation (Takahashi et al. 2009). Structure assignment of zamamidine A has revealed anN-2 ethylene bound �-carboline ring. Impressive cytotoxicity against P388 murine leukemia, with ahalf-maximal inhibitory concentration (IC50) of 13.8 �g/ml, is promising, despite the lack of in vitrocytotoxicity against KB human epidermoid carcinoma cells.



Structurally related to the manzamine alkaloids is the tetracyclic bis-piperidine alkaloid neopet-rosiamine A (18) (Wei et al. 2010). On the basis of its molecular formula, C30H52N2, 18 has six sitesof unsaturation. Neopetrosiamine A displays strong in vitro cytotoxicity against NCI’s panel of 60human tumor cell lines, with IC50 values of 1.5, 2.0, and 3.5 �M for MALME-3M melanoma cancer,CCRFCEM leukemia, and MCF7 breast cancer, respectively (Wei et al. 2010). Adding to the biomed-ical promise of 18 is its in vitro inhibitory activity against the pathogenic microbes Mycobacteriumtuberculosis and Plasmodium falciparum (Wei et al. 2010).

The marine actinomycete Streptomyces alkaloid splenocin A (19), isolated by Strangman et al.(2009), is a potent inhibitor of the cytokine production implicated in asthma. With a molecular formulaof C26H28N2O9, splenocin A has 14 degrees of unsaturation. The cyclic bis-lactone 19 is a potentinhibitor of pro-inflammatory cytokine production (IC50 = 3 nM) and has a biological profile compa-rable to that of the corticosteroid dexamethasone (IC50 = 5 nM) (Strangman et al. 2009). From theperspective of drug development, 19 is marked by exceptional biomedical promise as an antiasthmalead compound.

Plectosphaeroic acid A (20) is an alkaloid–diketopiperazine cultured from the fungus Plec-tosphaerella cucumerina, obtained from marine sediments collected in Barkley Sound, BritishColumbia (Carr et al. 2009). With a molecular formula of C25H45N3O6S, MDSM 19 has 27 sitesof unsaturation. The plectosphaeroic acid family is biosynthetically derived from four equivalents oftryptophan and one equivalent of either alanine or serine, followed by subsequent modification toyield the various analogues (Carr et al. 2009). Having inhibitory activity against the molecular tar-get of indoleamine 2,3-dioxygenase (IDO), 20 is a promising lead compound for anticancer agentsthat modify the ability of tumor cells to evade the T-lymphocyte-based immune response (Muller &Prendergast 2005).

The brominated-alkaloid (E,Z)-bastadin 19 (21) was isolated from a marine sponge, Lanthella cf.reticulata (Calcul et al. 2010), and is the diasteromer of known (E,E)-bastadin 19 (Mack et al. 1994).The molecular formula of 21 has been established as C34H27Br5N4O8, with 21 degrees of unsaturationand a core ratio H/C � 1. The presence of 2-hydroxyimino-N-alkylamide functionality is characteristicof bastadin metabolites, whereby the configuration about the oximo amide bonds is the basis of thediastereomeric relationship of 21. (E,Z)-bastadin 19 is the first reported (Z)-oximo amide bastadin. Theinherent instability of the Z-oximo amide configuration readily leads to isomerization of functionalityto the thermodynamically more stable E-isomer, which fact has been recently supported by molecularmodeling of macrocycle 21 (Inman & Crews 2011). The bastadins display an impressive bioactivity,including Ca2+ channel modulation (Inman & Crews 2011).

The chlorinated-alkaloid ammosamide A (22) belongs to the pyrroloiminoquinone class of naturalproducts and displays extraordinary atom diversity. It possesses a molecular formula of C12H10ClN5OSand 10 sites of unsaturation (Hughes et al. 2009b). MDSM 22 was cultured from a marine-derivedactinomycete, Streptomyces strain CNR-698, obtained from deepwater sediments in the BahamasIslands (Hughes et al. 2009b). As 22 has a core ratio of H/C � 1, it presents an awesome structuralchallenge, which is further compounded by the dense arrangement of the heteroatoms (N, O, S) andthe relative lack of hydrogen atoms. Thus, x-ray crystal analysis was ultimately responsible for thestructure assignment of 22 and led to the identification of the unusual thio-� -lactam ring. AmmosamideA is an encouraging MDSM, possessing potent in vitro cytotoxicity against HCT-116 colon carcinoma(IC50 = 320 nM), and has as its molecular target the myosin family (Hughes et al. 2009a). The totalsynthesis of ammosamide A and B was completed shortly after initial structure disclosure (Hughes &Fenical 2010b). A short review highlighting ammosamide MDSMs as modulators of the cell cycle hadalready been published (Zurwerra et al. 2010).

1.2.4 DepsipeptideThe cyclic depsipeptide largazole (23), isolated from a marine cyanobacterium, Symploca sp., collectedfrom Key Largo, Florida Keys, has a molecular formula of C29H42N4O5S3 and 11 sites of unsaturation(Taori et al. 2008). Largazole possesses significant atom and functional group diversity: substituted



4-methylthiazoline linearly fused to thiazole and thioester functionality. Cyanobacteria metabolite 23 isa potent and selective cytotoxic agent, with nanomolar activity against various epithelial and fibroblasticcancer cell lines (Taori et al. 2008). Its structural complexity and biological activity have made it anattractive candidate for total synthesis. Just a few months after the initial disclosure, the total synthesis of23 was completed and its molecular target was identified (Ying et al. 2008). Remarkably, the therapeuticprofile of 23 is attributed to the selective molecular inhibition of class I histone deacetylases (HDACs)overexpressed in cancer cells (Hong & Luesch 2012). Additional analysis and discussion of 23 as achemical probe will be given in Section 1.4.

1.2.5 Polyketide–peptideA culture of the marine cyanobacterium Symploca sp. led to the isolation of a new class of proteasomeinhibitors, represented by carmaphycin A (24) (Pereira et al. 2012). Having a molecular formula ofC25H45N3O6S and five sites of unsaturation, 24 displays an appreciable degree of chemical diversity. Itsconsists of two unusual structural elements: an �,�-epoxyketone “warhead” and methionine sulfoxidefunctionality (1 : 1; R-S-sulfoxide diastereomers). The cyanobacterial peptide 24 inhibits extracellularsignal-regulated protein kinase (ERK) phorphorylation of the �5 subunit of Saccharomyces cerevisiae20S proteasome with “chymotrypsin-like activity” (Groll et al. 2000). Pereira et al. (2012) speculatethat the sulfoxide is the structural element responsible for the observed bioactivity.

The thiazole-containing brominated–peptide bisebromoamide (25) displays a striking degree ofatom diversity, with a molecular formula of C51H72BrN7O8S and 19 sites of unsaturation (Teruyaet al. 2009). Like the cyanobacterial metabolites, 25 possesses a combination of D-amino acid andN-methylated residues, along with nonribosomal derived moieties (Teruya et al. 2009). Having potentcytotoxicity against 39 human cancer cell lines (JFCR39 panel at the Japanese Foundation for CancerResearch), yielding an average GI50 of 40 nM across the tested strains, bisebromoamide is a compellingMDSM ideally suited for total synthesis and biological exploration. Gao et al. (2010) disclosed itsfirst total synthesis and stereochemical reassignment. Later, Sumiya et al. (2011) reported a methodfor cell morphological profiling of natural product libraries, whereby 25 was identified as an actinfilament stabilizer.

1.3 A VIEW BASED ON STEREOCHEMICAL DIVERSITY

Eleven structures are presented in Table 1.3 and Figure 1.5 to illustrate the outstanding stereochemicaldiversity of MDSMs, compiled according to biosynthetic classes. The structures included in Table 1.3are derived from the two most prolific groups: sponges and bacteria. To highlight the stereochemicaldiversity between the structural classes represented in Table 1.3, the number of defined stereocentersand E,Z-olefins has been included. Comments are given to provide additional perspective and directthe reader to salient features of this group of MDSMs.

1.3.1 TerpeneMonamphilectine A (26) is an unusual diterpenoid alkaloid isolated from a marine sponge, Hymeniaci-don sp., obtained from Mona Island, of the Puerto Rican archipelago (Aviles & Rodrıguez 2010).MDSM 26 exhibits a rare marine-derived �-lactam moiety (Anthoni et al. 1987), in combination withan amphilectane-base carbon framework. Semisynthesis has been used to confirm the structure assign-ment and absolute configuration of 26, which possesses seven chiral centers in very close proximity. Aremarkable, facile, one-pot, multiple-component synthesis has been developed (Domling & Ugi 2000).The unusual sponge metabolite 26 displays potent antimalarial activity. Its biomedical prospects willundoubtedly benefit from the effective one-pot synthesis, which addresses the supply challenge.



Table

1.3

Ase

lect

ion

of11

mar

ine-

deriv

edna

tura

lpro

duct

s,ill

ustra

ting

ara

nge

ofste

reoc

hem

istry

.

Entr

yN

atu

ralp

roduct

Org

anis

mso

urc

eBio

synth

etic

class

Ster

eoce

nte

rs/

E,Z

-ole

fins

Com

men

t

1M

onam

phile

ctin

eA

(26

)Sp

onge

Hym

enia

cido

nsp

.D

iterp

enoi

d–al

kalo

id7/

0Po

tent

antim

alar

ial�

-lact

amis

olat

edin

mill

igra

mqu

antit

ies.

Stru

ctur

eco

nfirm

edby

sem

isyn

thes

is.

2M

arin

omyc

inA

(27

)Bact

eriu

mM

arin

ispo

rasp

.Po

lyke

tide

10/1

0Po

tent

cyto

toxi

city

agai

nstm

elan

oma

canc

erce

lllin

es.S

igni

fican

tant

imic

robi

alac

tivity

agai

nstd

rug-

resi

stant

bact

eria

.3

Indo

xam

ycin

A(2

8)

Bact

eriu

mSt

rept

omyc

essp

.Po

lyke

tide

6/4

Sign

ifica

ntgr

owth

inhi

bitio

n(�

50%

ofgr

owth

)atc

once

ntra

tions

betw

een

0.3

and

3�

Mre

lativ

eto

cont

rol.

4Sp

ongi

statin

1(2

9a

)A

ltohy

rtin

(29

b)

Cin

achy

rolid

eA

(29

c)

Sponge

(10

a) S

pong

iasp

.,Sp

irastr

ella

spin

ispi

rulif

era ;

(10

b) H

yrtio

sal

atum

,H

alic

lona

sp.;

(10

c)C

inac

hyra

sp.

Poly

ketid

e–m

acro

lide

24/2

Isola

ted

inlo

wyi

elds

,0.0

03–0

.17

mg/

Kgfro

mfiv

edi

ffere

ntsp

onge

spo

sses

sing

nMin

vitro

activ

ityvs

.can

cerc

ells.

Synt

hesi

s:2

9a

=2

9b

.

5N

eope

ltolid

e(3

0)

Sponge

Dae

dalo

pelta

Solla

sPo

lyke

tide–

alka

loid

6/2

Nan

omol

arin

vitro

cyto

toxi

city

.Iso

latio

nby

Wrig

htin

2007

,with

tota

lsyn

thes

isan

dstr

uctu

ralr

evis

ion

bySc

heid

tin

2008

and

2009

.6

Taus

alar

inC

(31

)Sp

onge

Fasc

aply

sino

psis

sp.

Poly

ketid

e–al

kalo

id9/

6In

hibi

tspr

olife

ratio

nof

K562

leuk

emia

cells

.D

-and

L-am

ino

acid

resi

dues

.7

Mui

rono

lide

A(3

2)

Sponge

Phor

bas

sp.

Poly

ketid

e–ch

lorin

ated

-al

kalo

id8/

3M

icro

scal

estr

uctu

reel

ucid

atio

n(0

.09

mg)

.

8D

icta

zole

A(3

3)

Sponge

Smen

ospo

ngia

cere

brifo

rmis

Brom

inat

ed-a

lkal

oid

3/0

Inhi

bite

dBA

CE1

(mem

apsi

n2)

-med

iate

dcl

eava

geof

amyl

oid

prec

urso

rpro

tein

(APP

)in

ado

se-d

epen

dent

man

ner.

9M

arin

opyr

role

B(3

4)

Bact

eriu

mSt

rept

omyc

essp

.H

alog

enat

ed-a

lkal

oid

0/0

Axi

ally

chira

lcom

poun

dbi

osyn

thet

ical

lypr

oduc

edin

atro

p-se

lect

ive

enxy

mat

icca

taly

sis.

10C

oiba

mid

e(3

5)

Cyanobact

eriu

mLe

ptol

yngb

yasp

.D

epsi

pept

ide

13/0

Pote

ntan

dse

lect

ive

antip

rolif

erat

ive

with

apo

tent

ially

new

mec

hani

smof

actio

n.11

Palto

lide

A(3

6)

Sponge

Theo

nella

swin

hoei

Pept

ide

6/0

D-a

ndL-a

min

oac

iddi

strib

utio

n,su

gges

tive

ofcy

anob

acte

rialo

rigin

s.



Figure 1.5 A selection of 11 marine-derived natural products, illustrating a range of stereochemistry.

1.3.2 PolyketideA novel of marine actiomycetes Marinispora strain CNQ-140 led to the isolation of marinomycin A(27), which exhibits unusual polyene–polyol functionalitites (Kwon et al. 2006). Polyketide 27 exhibitsa high degree of stereochemical diversity, possessing 10 stereocenters and 10 E,Z-olefins, and is amongthe first class of marine natural products to possess the unusual polyene–polyol structure. Owing tothe hydroxylated and conjugated structural architecture, 27 exhibits atypical chiroptical properties.



Coplanar and opposing conformations of the polyene–polyol chains in 27 have been ascribed toconformational interactions, with this observation supported by reports of chirality in the absence ofchiral carbons, as observed for certain polyolefinic systems (Kwon et al. 2006). Marinomycin A displayspotent antimicrobial activity against antibiotic-resistant strains of methicillin-resistant Staphylococcusaureus (MRSA), with minimum inhibitory concentration required to inhibit growth of 90% of organisms(MIC90) of 0.13 �M, and against vancomycin-resistant Enterococcus faecium (MIC90 = 0.13 �M). Forcomparison, the gold-standard antibiotic vancomycin has a MIC90 of 0.95–0.391 �g/ml, while penicillinG has a MIC90 of 6.25–12.5 �g/ml (Kwon et al. 2006).

From the standpoint of addressing the resupply challenge of MDSMs, the total synthesis of mari-nomycin A has been reported (Nicolaou et al. 2006, 2007). Recently, a convergent total synthesis of 27was disclosed, which featured the chemoselective construction of the macrodiolide dimerization (Evanset al. 2012). The differing synthetic methodologies offer entry to material 27 for future antibacterialdrug development.

Indoxamycin A (28) is an unusual polyketide isolated from the novel marine actinomycete strainNPS-643, from Kochi Harbor, Japan. It possesses low homology (96%) to Streptomyces sp. (Sato et al.2009). Belonging to a class of novel tricyclic polypropionates, 28 exhibits tremendous stereochemicaldiversity: an impressive collection of six consecutive and highly congested chiral carbons and four E/Z-olefins. The unusual incorporation of propionates is noteworthy, and Sato et al. (2009) hypothesize thebiosynthesis of 28 to be an adaptation of NPS-643 to the marine habitat. Possessing cytotoxicity againstthe human colon adenocarcinoma HT-29 cell line (IC50 = 0.59 �M), 28 is an inspiring MDSM withbiological promise and significant stereochemical diversity. The total synthesis and stereochemicalreassignment of (±)-indoxamycin B has recently been reported by Jeker & Carreira (2012).

Spongistatin 1 (29a) ≈ altohyrtin (29b) ≈ cinachryolide A (29c) is a highly oxygenated polyketide–macrolide isolated in low yield from a collection of diverse marine sponges (Pietruszka 1998; Radjasaet al. 2011). With 24 stereocenters and two E,Z-olefins, spongistatin 1 displays tremendous stereochem-ical complexity. Polyketide–macrolide 29a has nanomolar in vitro activity in the screen of the NCIpanel of 60 cancer cells and remains an inspirational case of an MDSM with potent cytotoxicity. Giventhe therapeutic profile of 29a, synthetic efforts have addressed its resupply challenge, and highlightsfrom these strategies have been reviewed in the literature (Dalby & Paterson 2010; Qi & Ma 2011).

1.3.3 AlkaloidNeopeltolide (30) was isolated from the deepwater marine sponge Daedalopelta sollas in 2007 (Wrightet al. 2007). It possesses stereochemical complexity, which was not trivial to assign correctly, withnanomolar activity and specificity against cancer cell lines (A-549 human lung adenocarcinoma, NCI-ADR-RES human ovarian sarcoma, and P388 murine leukemia cell lines, with reported IC50 values of1.2, 5.1, and 0.56 nM, respectively) (Qi & Ma 2011). The compelling antiproliferative activity of 30necessitated total synthesis in order to address the resupply challenge. The first total synthesis of 30was accompanied by a structural revision and was reported by Custar et al. (2008). Shortly thereafter,the efficient coupled synthesis–SAR investigation of 30 was disclosed (Custar et al. 2009), and sincethen a multitude of other investigations have been published; these have been recently reviewed (Qi &Ma 2011).

The potent and selective cytotoxic tausalarin C (31) was isolated from a Madagascar sponge,Fascaplysinopsis sp., by Bishara et al. (2009). The polyketide–alkaloid tausalarin C is structurallyintriguing and demonstrates a high degree of stereochemical diversity: nine stereocenters and six E/Z-olefins. Biosynthetically, 31 is derived from the metabolites salarin A and taumycin A, which are alsoisolated from Fascaplysinopsis marine sponge (Bishara et al. 2008). Bishara and colleauges suggestthat the variability in chemical constitution and relative yield of Fascaplysinopsis metabolites, as wellas the structural similarity to other microorganism metabolites, intimates microbial associations fromthe host sponge (Bishara et al. 2009; Radjasa et al. 2011).

A remarkable case of a polyketide–chlorinated-alkaloid is muironolide A (32), isolated from themarine sponge Phorbas sp. by Dalisay et al. (2009). Muironolide A is a striking example of the



chemodiversity of macrolides from Phorbas sp. and demonstrates the successful isolation and structureelucidation of an MDSM on nanomole scale. Muironolide A possesses high stereochemical diversity,with eight stereocenters and three E,Z-olefins, which collectively make up the novel carbon frame-work, which includes a unique tricholoro-carbinol ester, trans-chlorocycloproane, and hexahydro-1H-isoindolone-triketide ring. Structure elucidation of 32 proceeded on 90 �g (152 nmol) of sample,employing microprobe nuclear magnetic resonance (NMR) spectroscopy (Dalisay & Molinski 2009).Dalisay et al. (2009) suggest that 32 might in fact be the biosynthetic product of microbial associa-tion with the host Phorbas sponge. The low-yield isolation of 32 necessitates total synthesis in orderto address the resupply challenge and allow for further biomedical investigation. Flores & Molinski(2011) have recently reported the synthesis of the isoindolinone core of 32, and further investigationsare underway.

The brominated-alkaloid dictazole A (33) was extracted from freeze-dried Panamanian marinesponge, Smenospongia cerebriformis, by Dai et al. (2010). The milligram isolation of 33 complementsan already-known class of sponge metabolites, the dictazolines (Dai et al. 2008). Dictazole A has threestereocenters tightly congested about the cyclobutyl core, and Dai et al. (2010) thus propose it to bethe biosynthetic precursor of the constitutional isomer dictazoline C by way of a vinyl cyclobutanerearrangement (Dai et al. 2010). Dictazole A is therapeutically relevant towards Alzheimer’s disease,where it inhibits the aspartic acid protease �-secretase 1 BACE1 (memapsin 2), implicating the neurode-generative disease (Hardy 2006). The 2-iminoimidazolidinone of 33 is the presumed pharmacophoreresponsible for BACE1 (Hills & Vacca 2007). Taken together, 33 displays tremendous biomedicalpotential and warrants further investigation.

Marinopyrrole B (34) was cultured from a sediment-derived salt obligate marine actinomycete,Streptomyces sp. strain CNQ-418, obtained from La Jolla, California (Hughes et al. 2008). Havinga molecular formula of C22H11BrCl4N2O4 and 16 degrees of unsaturation, MDSM 34 presented asignificant structural challenge due to a core ratio of H/C � 1. Ultimately, the structure assignment ofmarinopyrrole B was established on the basis of x-ray crystallography data. Of interest to the presentdiscussion is that marinopyrrole B is axially chiral and was isolated as a single atrop-enantiomer, whichwas assigned M-configuration on the basis of x-ray Flack parameter (Hughes et al. 2008). MDSM 34displays antibacterial activity against MRSA (MIC90 � 2 �M) (Hughes et al. 2009c, 2010; Haste et al.2011). Nicolaou et al. (2011) disclosed the total synthesis of the structurally related marinopyrrole Aand the accompanying biological evaluation of marinopyrrole analogues.

A striking feature of marinopyrrole B is the presence of an unprecedented bispyrrole structure(Hughes et al. 2008). Yamanaka et al. (2012) recently reported an elegant study encompassing char-acterization of the flavoenzyme responsible for catalysis of the atrop-selective N,C2-bipyrrole homo-coupling in the biosynthesis marinopyrroles. Two flavin-dependent halogenases were identified on amolecular basis as being responsible for the biosynthetic atrop-selective N,C-bipyrrole homocouplingin the novel class 1,3′-bipyrrole 34.

1.3.4 DepsipeptideThe cyclic depsipeptide coibamide A (35) was isolated from a marine-derived cyanobacterium,Leptolyngya sp., from Panama, by Medina et al. (2008). Depsipeptide 35 has a total of 13 stereo-centers and an appreciable degree of stereochemical diversity. Substantial N- and O-methylation of35 is consistent with its being of cyanobacterial origin. Coibamide A displays potent and selectivecytotoxicity when tested in a panel of NCI 60 cell lines, with a pattern of activity for breast, centralnervous system (CNS), colon, and ovarian tumor cells. Significant cytotoxicity (50% lethal concentra-tion (LC50) � 23 nM) has been observed for NCI-H460 human lung tumor cells and mouse neuro-2acells. The therapeutic profile of coibamide A is inspirational from the perspective of further biomedicalinvestigation. Also promising is the extensive N-methylation present in 35, which may benefit fromimproved pharmacological properties and drugability as compared to standard peptides (Morishita &Peppas 2006).



1.3.5 Polyketide–peptideThe cyclic hexapeptide paltolide A (36) was isolated from a deepwater specimen of the marine spongeTheonella swinhoei, from Palau, by Plaza et al. (2010). MDSM 36 is characterized by a C-terminaltryptophan moiety linked to the ε-amine of a D-lysine, which is consistent with a rare subgroup ofthe sponge-derived anabaenopeptins (Grach-Pogrebinsky & Carmeli 2008). Paltolide A has six chiralcenters, in which the presence of a distribution of D- and L-amino acids is suggestive of cyanobacterialorigin. Further support for this notion is the fact that anabaenopeptins have been isolated from bothsponges and cyanobacteria (Fisch et al. 2009; Christiansen et al. 2011).

1.4 CASE STUDIES OF CHEMICAL PROBES AND CHEMICALPROBES IN THE THERAPEUTIC DISCOVERY PIPELINE

This section develops on the earlier discussion of MDSMs as chemical probes. Analysis of the peer-reviewed publication record using SciFinder® (http://www.cas.org/products/scifinder) provides thebasis for the case studies and allows a perspective to be developed on the biomedical prospects of theseselect MDSMs as chemical probes. Three illustrative examples of MDSM classes have been selected:(1) the actin-binding marine macrolide latrunculin A (12); (2) the proteasome inhibitor salinosporamideA (6); and (3) the histone deacetylase inhibitor largazole (23). The MDSM chemical probes discussedin this section are introduced in chronological order of first isolation.

Figure 1.6 shows a histogram of peer-reviewed publications on latrunculin A, salinosporamide A,and largazole classes of MDSMs, from the year of isolation to 2011.

The story of the sponge metabolite latrunculin A begins in the early 1970s, when sponge juicesfrom Negombata magnifica and Cacospongia mycofijiensis were identified as cytotoxic (Neeman et al.1975). Isolation of the sponge extracts identified latrunculin A as the active agent and eventuallyled to realization of the molecular target (Groweiss et al. 1983). Concurrent in vitro investigationsrevealed that latrunculin A interferes with mammalian actin microfilament organization (Spector et al.1983). A significant finding was reported in 1997, when 12 was shown to effectively interfere withSaccharomyces cerevisiae actin cytoskeleton in under 5 minutes (Ayscough et al. 1997). Around

250

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Latrunculin (12)

Salinosporamide (6)

Largazole (23)

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Figure 1.6 Histogram of peer-reviewed publications on latrunculin A (12), salinosporamide A (6), andlargazole (23) classes of marine-derived natural products, from the year of isolation to 2011 (data basedon search of SciFinder® ). (For a color version of this figure, please see the color plate section.)



this same time, latrunculin A became commercially available as a chemical probe, which has sincecontributed to the upward trend in the number of peer-reviewed publications surrounding it.

A second example of an inspirational MDSM chemical probe is represented by the proteasomeinhibitor salinosporamide A class. Salinosporamide A is among the drug candidates from the Actino-mycetales order with the most potential and is presently in phase I evaluation as an anticancer agent(Fenical et al. 2009; Lechner et al. 2011). Like latrunculin A, salinosporamide A is commerciallyavailable as a chemical probe, used to target biological proteosome function and inhibition (Kim &Crews 2008; Kale et al. 2011). The plot of Figure 1.6 shows the steady increase in the number ofpeer-reviewed publications on the salinosporamide A class.

The histogram of largazole suggests that exploration of this MDSM is in its infancy, but it isnevertheless a popular subject of synthetic inquiry and biological investigation (Taori et al. 2008).Largazole has benefitted from a nearly simultaneous isolation/total synthesis (four months betweenpublications) by the Luesch group (Ying et al. 2008), providing it with a larger than average numberof peer-reviewed publications in its first year (17 publications reported in 2008). Although 23 isnot commercially available at this time, its compelling biological activity as an HDAC inhibitor hascaptured the interest of the synthetic community and has contributed to a high incident of publication(Bowers et al. 2008, 2009). Hong & Luesch (2012) recently reviewed the literature surrounding thesynthesis and development of largazole as a broad-spectrum agent. What remains most inspiring is theisoform selectivity of largazole for class 1 HDAC inhibition. Present efforts in the chemical biologycommunity are largely directed at defining the molecular basis of largazole isoform-selective HDACinhibition, with future research predicted to be directed at designing additional largazole analoguesthat possess the same, if not improved, selectivity profile (Hong & Luesch 2012).

1.5 CONCLUSION

The MDSMs highlighted in this account reinforce the biomedical promise and importance of marine-derived secondary metabolites and demonstrate an astounding chemical and functional diversity. Asignificant case for future exploration of underexplored taxa, particularly marine microorganisms, isgreatly supported by this account. The resupply challenge has been effectively addressed for manyof the MDSMs presented here, although others continue to wait for similar success. The interplaybetween total synthesis and structural reassignment alluded to has added further value to organicsynthesis efforts, beyond purely allowing entry to material for clinical investigation and/or development.MDSMs are employed as powerful chemical probes used to understand biological function, andthey will be especially useful once the resupply challenge is overcome and they achieve commercialavailability. Microbial associations and/or marine-invertebrate associations offer powerful direction forfuture investigations, especially by way of collaborative and interdisciplinary interactions between themarine natural products, marine microbiology, synthetic, and biomolecular engineering communities.

ACKNOWLEDGMENTS

The authors thank the NIH Project Research Grant R01 CA047135 and Administrative ResearchSupplement to R01 CA047135 (Y.M.V.) for the support received in P.C.’s laboratory.

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