5-Amino-2-aroylquinolines as Highly Potent Tubulin Polymerization Inhibitors. Part 2. The Impact of Bridging Groups at Position C-2

Abstract

A variety of studies on the modification of combretastatin A-4 triggered our interest in the impact of the linkers between the 3,4,5-trimethoxyphenyl ring and 5-amino-6-methoxyquinoline on biological activity. The replacement of the carbonyl group with bond, amine, ether, sulfide, and sulfone groups was evaluated in this study. The results showed that compounds 14 and 15 containing sulfide and sulfone groups between the 3,4,5-trimethoxyphenyl ring (A-ring) and 5-amino-6-methoxyquinoline exhibited substantial antiproliferative activity against KB, HT29, and MKN45 cells with mean IC50 values of 42 and 12 nM, respectively. 15 inhibited the tubulin polymerization with an IC50 value of 2.0 μM, similar to that with CA4. The continued work on the C-5 substituents of 3',4',5'-trimethoxybenzoyl-6-methoxyquinoline derivatives demonstrated that compound 7 possessing OH at C-5 exhibited excellent antiproliferative activity with mean IC50 values of 3.4 nM and microtubule destabilizing potency with an IC50 of 1.5 μM, comparable to that of CA4 (IC50=1.9 μM). It also exhibited substantial vascular disrupting effects. Compounds 7 and 15 exhibited significant efficacy against MDR/MRP-related drug-resistant cell lines (KB-vin10, KB-S15, and KB-7D) with mean IC50 values of 6.7 and 2.6 nM, respectively.

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

“…Compound 87 exhibited more potent inhibition of tubulin polymerization (IC 50 =1.6 μM) than CA-4 (IC 50 = 2.1 μM) and showed strong binding property to the colchicine binding site on microtubules. A continued modification of the linkers (-O-, -NH-, -S-, -SO 2 -, and direct bond) between TMP and 5-amino-6-methoxyquinoline identified active oxygen and sulfur atom linked analogs ( 88-90 ) (84). Although less active than parent compound 87 , the most potent compounds, sulfide 89 and sulfone 90 , still showed low nanomolar inhibition against cancer growth and revealed that the linkage has a capacity for various bridging groups.…”

Combined Molecular Docking, 3D‐QSAR, and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine‐binding Site

“…Chem. website and curated sixteen important medicinal chemistry papers (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) carefully for analysis of the structure-activity relationship (SAR) and the binding pose of these ligands (Chart S1). From the year 2004-2012, Silvestri group (18-23) reported a series of colchicine-site inhibitors with arylthioindole skeleton, and recently their attentions were shifted to the replacement of the indole ring with thiazole (24,25).…”

“…Second, how to carry on the modifications of B and C region heavily depended on the structure of the parent nucleus (indol, thiophene, thiazole, or other else). The common electron-donating group such as hydroxy, methoxy, amino or halo substituent can be employed at this site for enhancing potency (18)(19)(20)22,(26)(27)(28)(29). The difference of modification on B and C area between these lead compounds was merely the various position of the parent core.…”

Combretazet-3 a novel synthetic cis-stable combretastatin A-4- azetidinone hybrid with enhanced stability and therapeutic efficacy in colon cancer

“…These findings are in agreement with a recent report by Schobert et al (12) demonstrating improved activity of oxazole bridged CA-4 analogues by substitution of the B-ring phenolic group with H, fluoro or amino groups. Also, substitution of the ethylene bridge with a sulfone group coupled with the substitution of B-ring with a 5-amino-6-methoxyquinoline moiety yielded a novel compound with activity in the low nanomolar range in HT-29 cells (IC 50 =16 nM) (20). Ring B 4-ethoxyphenyl 1,5-diaryl substituted 1,2,3,4-tetrazoles also displayed potent activity in HT-29 cells (21).…”