Synthesis, cytotoxic activity, and SAR analysis of the derivatives of taxchinin A and brevifoliol

Abstract

Twenty-one derivatives of taxchinin A (1) and brevifoliol (2) were synthesized and evaluated for cytotoxicity against human non-small lung cancer (A549) cell line. Nine derivatives showed potent activity with IC(50) values from 0.48 to 6.22microM. 5-Oxo-13-TBDMS-taxchinin A (11) and 5-oxo-13,15-epoxy-13-epi-taxchinin A (15) are the most potent derivatives, with IC(50) at 0.48 and 0.75microM, respectively. The structure-activity relationship (SAR) of these compounds established that exocyclic unsaturated ketone at ring C is the key structural element for the activity, while the alpha,beta-unsaturated ketone positioned at ring A has no effect for the activity. The significant cytotoxicity of derivatives 11 and 15 may be due to the conformational change in the taxane rings. The 3D-QSAR study was conducted on this series of compounds, which provided optimal predictive comparative molecular field (CoMFA) model with cross-validated r(2) (q(2)) value of 0.64.

Dual-Functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-κB Activation

“…Compound 4 was prepared from taxchinin A ( 2 ) in 85% overall yield in two steps using the optimized procedure we reported previously. 8 Initially, OH-13 of 2 was protected selectively by treatment with tert -butyldimethylchlorosilane (TBDMSCl) in imidazole and DMF. Later, the yield was increased to 90% by lowering the reaction temperature to −40 °C.…”

“…Syntheses of compounds 9 – 14 and 16 – 17 are shown in Scheme . Compound 4 was prepared from taxchinin A ( 2 ) in 85% overall yield in two steps using the optimized procedure we reported previously . Initially, OH-13 of 2 was protected selectively by treatment with tert -butyldimethylchlorosilane (TBDMSCl) in imidazole and DMF.…”

“…Unfortunately, taxchinin A is totally inactive against tumor cell line proliferation. In subsequent studies, we found that analogues containing taxchinin A as the core template but possessing an exocyclic unsaturated ketone in ring C exhibited satisfactory cytotoxicity . To date, the mechanisms associated with the inhibitory effects of these compounds against cancer cell proliferation have not yet been disclosed.…”