medicinal-chemistry-toxicology-2018-posters

Medchem & Toxicology 2018

Page 67

Journal of Organic & Inorganic Chemistry

ISSN: 2472-1123

A n n u a l C o n g r e s s o n

Medicinal Chemistry,

Pharmacology and toxicology

J u l y 3 0 - 3 1 , 2 0 1 8

Am s t e r d a m , N e t h e r l a n d s

AK1 is the major oncogenic/ageing Ser/Thr kinase that is activated by p21 (RAC/CDC42) and several other signal transducers

such as PIX, three distinct Tyr-kinases (ETK, FYN and JAK2) and CK2 (casein kinase 2) in cells. PAK1 is essential for robust

growth of almost all solid tumors which require PAK1-dependent angiogenesis. Besides this, kinase is required for many other

diseases/disorders such as NF (neurofibromatosis), AD (Alzheimer’s disease), PD (Parkinson’s disease), depression, epilepsy,

autism, schizophrenia, a variety of infectious and inflammatory diseases, diabetes (type 2), obesity, and even hyperpigmentation.

Thus, the potential maket value of PAK1-blockers is enourmous. However, so far only a few PAK1-blockers are available on

the maket, such as FK228, Gleevec, and the old antibiotic called minocycline (MC) but with a very limited FDA approval for

cancer therapy. Thus, for a last decade, we have taken a great effort for identifying PAK1-blockers among natural or old (generic)

products as well as the robust potentiation of their anti-cancer/anti-PAK1 activity mainly by increasing their cell-permeability.

Here in this lecture, we shall introduce a few successful examples including 1,2,3-triazolyl esters of natural or generic COOH-

bearing PAK1-blockers such as UA (ursolic acid), ARC (artepillin C), CA (caffeic acid), Ketorolac and MPA (mycophenolic acid),

in which esterization by a simple reaction called CC (Click Chemistry) boosts their anti-cancer potential by 100-5000 times,

depending on target cancer cell lines and the final chemical products. One of them called “15K” (ketorolac ester) has been proven

to be among the most potent PAK1-blockers, suppressing the embryonic angiogenesis

in ovo

(fertilized chicken eggs) IC

around

1 nmol/egg, and extending significantly the healthy lifespan of

C. elegans

by 30% at 50 nM, strongly suggesting that they could

cure most of solid tumors without any severe side effect.

Boosting the anti-cancer potential of COOH-bearing

PAK1-blockers by increasing their cell-permeability

via click chemitry

Hiroshi Maruta

PAK Research Center, Melbourne, Australia

J Org Inorg Chem 2018, Volume 4

DOI: 10.21767/2472-1123-C3-009

Figure:

Click- Chemistry for Synthesis of Triazolyl Esters