Lesson 5: Triazolylation of "Acidic" Herbal PAK1-blockers for Improving Their Cell-permeability

There are a variety of  "acidic" herbal compounds that block the oncogenic/ageing kinase PAK1.
They include CA (caffeic acid) and ARC (artepillin C) from propolis, UA (ursolic acid) and RA (rosmarinic acid) from Rosemary leaves, and so on.  The major problem for their clinical application is their poor cell-permeability. Their COOH keeps these molecules "acidic", and this acidicity (negative charge) hampers their efficient penetration through the "acidic" (phospholipid-based) cell membranes.

In the case of CA,  phenethyl esterization of its COOH (converting to CAPE) significantly improves its cell-permeability.  That is why CAPE is 10 times more potent than CA as a PAK1-blocker in cell culture. However, this type of esterization significantly reduces its water-solubility, and therefore its bioavailability (absortion through intestine) in vivo.

Recently, owing to the potentially Nobel-winning "Click Chemistry" (invented by the 2001 Nobel laureate, Barry Sharpless) , which allows us to couple the "water-soluble" triazole ring to OH of the COOH moiety of these acidic herbal PAK1 blockers in a very high yield with copper salt as a catalyzer, an Indian group managed to improve the cell-permeability of a triterpene called UA by 200 folds (lowering the IC50 below 100 nM in cell culture) (1). 

Furthermore, a Chinese group managed to replace OH at position 3 of UA by amine, adding a "positive" charge (for improving its cell-permeability), and enhaunced its anti-cancer activity by 20 folds (2).  In theory, if we could combine these two "specifics", UA's IC50 in cell culture could be lowered to around 5 nM.  I believe a similar modification could be applied to many other acidic herbal PAK1-blockers for a robust improvement of both their cell-permeability and bioavailability.

In fact we recently managed to boost the cell-permeability (=anti-cancer activity) of an acidic PAK1-blocker (Ketorolac) over 500 times by the "Click Chemistry" (3, and US patent).

References:

1.      Rashid S, Dar BA, Majeed R, Hamid A, Bhat BA. See comment in PubMed Commons belowSynthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents. Eur J Med Chem. 2013 ; 66:238-45. 

2.   Ma CM, Cai SQ, Cui JR, Wang RQ, Tu PF, Hattori M, Daneshtalab M. The cytotoxic activity of ursolic acid derivatives. Eur J Med Chem. 2005; 40 (6): 582-9.

3.   Nguyen BC¹, Takahashi H², Uto Y², Shahinozzaman MD¹, Tawata S³, Maruta H⁴. 

      "Click Chemistry"-based highly potent PAK1-blocking cancer-killer. Eur J Med Chem. 2016 ;126:270-276.