Synthesis and biological evaluation of (1-aryl-1H-pyrazol-4-yl) (3,4,5-trimethoxyphenyl)methanone derivatives as tubulin inhibitors

Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities

“…Compound 12b exhibited the highest activity with an average IC 50 of 50 nM which is slightly better than that of colchicine (IC 50 = 65 nM), indicating that the 4-substituted indolyl moiety is optimal for activity ( 12b vs 12a and 12c ) in comparison to the 3- and 5-substituted indolyl groups. Series 4 compounds ( 14a–d ) showed low activity (IC 50 > 10 μM) probably due to their “straight” conformation which is not preferred for binding to the colchicine-binding site in tubulin as compared to the “bent” conformation of series 3 compounds; similar results were also observed by Zhang’s group . Series 5 compounds ( 23a–h ) demonstrated high antiproliferative activities with IC 50 values in the low nanomolar to low micromolar range.…”

“…Series 2 was designed by switching the positions of the C-ring and A-ring of series 1. Series 3 (“bent” conformation) and series 4 (“straight” conformation) were designed by shifting the positions of the A-ring to explore the preferred conformations by the binding pocket . Series 5 was designed by replacing the oxygen atom of the 3′-methoxy moiety with a selenium as selenium-containing compounds have been proven to be potent tubulin inhibitors. , In summary, the main strategy is to fuse the B-ring and cyclized ketone as the ring-fusion strategy is a common approach used in medicinal chemistry for drug design. , Here, we describe the design, synthesis, and biological evaluation of novel benzimidazole and indazole analogues as potential anticancer agents targeting tubulin polymerization.…”

“…Series 3 ("bent" conformation) and series 4 ("straight" conformation) were designed by shifting the positions of the A-ring to explore the preferred conformations by the binding pocket. 36 Series 5 was designed by replacing the oxygen atom of the 3′-methoxy moiety with a selenium as selenium-containing compounds have been proven to be potent tubulin inhibitors. 37,38 In summary, the main strategy is to fuse the B-ring and cyclized ketone as the ringfusion strategy is a common approach used in medicinal chemistry for drug design.…”

“…Series 4 compounds (14a−d) showed low activity (IC 50 > 10 μM) probably due to their "straight" conformation which is not preferred for binding to the colchicine-binding site in tubulin as compared to the "bent" conformation of series 3 compounds; similar results were also observed by Zhang's group. 36 Series 5 compounds (23a−h) demonstrated high antiproliferative activities with IC 50 values in the low nanomolar to low micromolar range. In this series, compounds bearing an indolyl A-ring (e.g., 23a, 23e, and 23g) showed significantly better antiproliferative activities (IC 50 ranging from 91 to 856 nM) than those with a phenyl A-ring (e.g., 23d, 23f, and 23h, IC 50 ranging from 3 to 10 μM), consistent with our previous observations that the indolyl A-ring is optimal for activity.…”

Structure–Activity Relationship of Cytotoxic Natural Products from Indonesian Marine Sponges

“…The unwanted cytotoxicity against normal mouse fibroblast (NIH3T3) was also found on 35 and 36 by only 25% and 29% growth, respectively. This similarity indicates that the isolated ketoxime group is essential for the compound’s cytotoxic selectivity on cancer cells (Zhai et al 2018 ; Tuccinardi et al 2013 ). This selectivity is also shown by compound 33 with a similar ketoxime group as compound 31 and 32 .…”