International Research for Global Health NAEJA Pharmaceutical Inc. INTEGRATED MEDICINAL CHEMISTRY.
MEDICINAL CHEMISTRY RESEARCH
Transcript of MEDICINAL CHEMISTRY RESEARCH
MEDICINAL CHEMISTRY RESEARCH
Development of TK inhibitors
Andrej Boháč
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Protein kinases (PK) – enzymes that transfer PO3 group to proteins
Protein Kinasesdirect the activity of up to30% of cellular proteins,orchestrate the activity ofalmost all cellularprocesses
Kinom (the kinase dendrogram)518 hu-PK collected in 7major groups. 6 subgroupsare serine / threonine kinasisand 1 group are TKs thatphosphorylate tyrosine AAresidues.
Manning G et al. 2002 Science 298 1912–34.KINOME shows diversity of catalytic domains
in 518 hu-PKPDF created with pdfFactory Pro trial version www.pdffactory.com
OUR RECENT RESULTS – SBCP / nM1. we developed para substituted AAZ-based inhibitors / and uncovered SBCP
(Salt Bridge Containing Pocket)
Struct. Chem. 2011, 22, 635. + unpublished resultsPDF created with pdfFactory Pro trial version www.pdffactory.com
2. We developed chimeric nM inhibitor / 34 VEGFR2 TK analysed / rare inactive (DFG-out) TK A-loop opened variants uncovered
European Journal of Medicinal Chemistry 72 2014 146-159.
OUR RECENT RESULTS – nM / rare variants of TKs
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OUR RECENT RESULTS – isosteric VEGFR2 modulators / Spider-like molecules3. Development of YNAMIDEs based triazolic VEGFR2 modulators/ Spider-like
(CRAAC) molecules proposed
ONH
N
O
N
S OO
AAZ (FW: 435.50)
IC50 = 22 nM (VEGFR2)docking score -50.3 (-51.6)
ISOSTERIC REPLACEMENT
Spider-like (CRAAC) molecules
NOVELTY, SYNTH FEASIBILITY
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OUR RESEARCH in progress
4. Regioisomeric Bioisostery (OXAZOLES, BENZOXAZOLES, CARBOXAMIDES)
5. Carboxamide VEGFR2 modulators
6. Benzoxazole VEGFR2 modulators
7. TAM TK (Mer TK) inhibitors development from 8 M structures(in vitro TK and cell assays)
8. 1,2,3-triazolic TK inhibitiors , In situ Click Chemistry, [2+2+2] cyclotrimerisations etc.
ONH
N
O
SO O
N
AAZ (17 nM (VEGFR2), PDB: 1Y6A)
overall yield ca 10 %stability, novelty
NH
N
O
S OO
O
ON
R
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Project: Methodology for a simple benzoxazolesynthesis useful for VEGFR2 inhibitors
development
Biomagi RNDr. Ambroz Almássy, PhD.PDF created with pdfFactory Pro trial version www.pdffactory.com
Project rationale
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Proposed sequential and one pot methodology
HO
ONH2
OH
+
AI
O
NHOH
EDCHOBt
A/ Synthesis of AmidicIntermediate and optimisation of its cyclisation
N
O
BO-PR
DEAD / PPh3
HO
ONH2
OH
+
AI
O
NHOH
EDCHOBt EDC / PPh3
Me3Al
EDC / PPh3
B/ one pot Synthesis of BenzoxazOl-PRoduct directly from aminophenol and ArCOOH
or DEAD / PPh3
Me3Al (excess, heating, ?)
Me3Al(excess, heating, ?)
1d
1a1b
1c
2c
2aaccording the lit. by this way also 8 %of benzoxazole was observed
2b
3H+
or Deoxo-Fluor reagent NSF3
OO 2d
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Mechanism of Mitsunobu ring closure
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Twice RegBioisostery
O
NHO
SOO
N
NO
Z
O
NHO
SOO
N
NO
Z
N
NHO
SOO
O
NO
Z
N
NHO
SOO
O
NO
Z
RegBio => four novel compounds possessing similar bioactivity
O
NHO
SOO
N
NO
Z
O
NHO
SOO
N
NO
NNHO
SOO
O
N
O
NNHO
SOO
O
N
OZ Z
Z
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in Silico predicted structures / Biomagi
O
NHO
SOO
N
N
OO
O
-53.28 (1Y6B)4 HB, FW 457, xlogP 3.6charges 0, NRB 8
O
NHO
SOO
N
N
O O
O
-53.25 (1Y6B)4 HB, FW 457, xlogP 3.6charges 0, NRB 8
O
NHO
SOO
N
N
OHO
O
-48.90 (1Y6B)4 HB + ?ionic, FW 443, xlogP 3.3charges -1, NRB 7
NH
N
O
S
O
OO NO
OHO
-47.81 (1Y6B)4 HB + ?ionic, FW 443xlogP 3.3, charges -1, NRB 7
HONH2OH
H2N
COOMe COOMe
[CPR]250 mg / 51 E
[CPR]250 mg / 51 E
HONH2OH
H2N
COOH COOH
[1571-72-8]5 g / 29 E
[2374-03-0]5 g / 81 E
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Aims for a Bc Diploma Work
1. Search of databases and literature for a direct preparation of benzoxazolesfrom karboxylic acids. Select the best methods for our purposes.
2. Develop of synthetic methodology for bezoxazole preparation directly fromArCOOH by simple and mild reaction conditions
3. Synthesis of some predicted benzoxazolic VEGFR2 inhibitors
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AcknowledgementDoc. RNDr. Marta Sališová, PhD. (retired)RNDr. Ambroz Almássy, PhD.p. Miroslava MatejováMgr. Lucia Kušnierová – Kováčiková, PhD. (SAV)Mgr. Lucia Lintnerová, PhD. (FaF UK)Mgr. Jana HolekšiováMgr. Juraj DobiašMgr. Peter ŠramelBc. Miroslav MurárKristína FerenczyováMarek OndrušMatúš HlaváčIvan Mäsiar
Biomagi, APVV, VEGA, COST CM1106
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Biological Target
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