Discovery and Optimization of Novel 5-Indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrile Derivatives as Potent Antitubulin Agents Targeting Colchicine-binding Site

Abstract

Aiming at development of potent antitubulin agents targeting colchicine-binding site, a series of novel 5-indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrilederivatives (5a–5v and 7a–7h) were designed based on bioisosterism and hybridization strategies. All these compounds were concisely synthesized via a three-step process and examined against five human cancer cell lines (HT-29, A549, MKN-45, MDA-MB-231 and SMMC-7721) along with a normal human cell (L02) in vitro. A structure-activity relationships (SARs) study was carried out and optimization towards this series of compounds in cellular assay resulted in the discovery of 5k, which displayed similar or better antitumor potency against the tested cancer cells with IC50 value ranging from 0.02 to 1.22 μM superior to CA-4 and Crolibulin. Significantly, a cell cycle study disclosed the ability of 5k to arrest cell cycle at the G2/M phase, and immunofluorescence assay as well as a colchicine competition assay revealed that tubulin polymerization was disturbed by 5k by binding to the colchicine site. Moreover, the molecular modeling mode showed the posture of 5k and Crolibulin was similar in the colchcine-binding pocket of tubulin as identified with the SARs and pharmacological results. Together, all these results rationalized 5k might serve as a promising lead for a novel class of antitubulin agents for cancer treatments.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…As such, several VDAs have been tested in combination with additional therapies [ 11 , 41 ], including radiotherapy [ 41 , 42 , 43 , 44 , 45 , 46 ], antiangiogenic agents (such as bevacizumab) [ 47 , 48 ], traditional cytotoxic chemotherapy (e.g., carboplatin, paclitaxel) [ 41 , 49 , 50 , 51 , 52 , 53 , 54 ] and recently immunotherapy [ 55 , 56 ]. There is a current resurgence of interest in VDAs and frequent reports describe novel agents, many based on the colchicine/combretastatin motif [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] ( Figure 2 A). These molecules are typically hydrophobic and are modified as phosphate prodrugs to enhance aqueous solubility and allow ease of delivery.…”

Pyrrolo-imidazo[1,2-a]pyridine Scaffolds through a Sequential Coupling of N-Tosylhydrazones with Imidazopyridines and Reductive Cadogan Annulation, Synthetic Scope, and Application

“…9.45 (d, J = 6.9 Hz, 1H), 7.81 (d,J = 8.8 Hz,1H),1H),7.25 (d,J = 6.8 Hz,1H),7.20 (d,J = 8.3 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.76 (d,J = 7.6 Hz, 1H), 6.47 (t, J = 4.5 Hz, 1H), 2.94 (t, J = 8.0 Hz, 2H), 2.52 (td, J1 = 7.9, J2 =4.9 Hz, 2H). 13 C{1H} NMR (75 MHz, CDCl3) δ (ppm): 149.4, 145.3, 135.5 (2C), 132.9, 132.2 (2C), 130.6, 127.9, 127.8, 127.5, 126.4, 123.4, 118.3, 116.5, 27.7, 23.5 imidazo [1,2-a] 1484, 1438, 1382, 1367, 1335, 1314, 1270, 1212, 1127, 765, 9,132.4,130.8,128.3,127.9 (2CH),126.5,125.8,125.5,118.5,116.8,25.2 (SCH2).…”

“…Methoxyphenyl)ethylidene)-4-methylbenzenesulfonohydrazide (1d) 21. white solid (1.52 g, 96%); mp 168-170 °C; 1 H NMR (300 MHz, CDCl3) δ (ppm): 7.92(d, J = 8.0 Hz, 2H),7.74 (s, 1H), 7.60(d, J = 8.6 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.81…”

“…white solid(1.58 g, 98%); mp 155-156 °C; 1 H NMR (300 MHz, CDCl3) δ (ppm): 8.01 (s, 1H), 7.91(d, J = 8.2 Hz, 2H), 7.57(d, J = 8.5 Hz, 2H), 7.31 (t, J = 7.6 Hz, 4H), 2.41 (s, 3H), 2.14 (s, 3H); 13 C{1H}…”

“…, 1384, 1370, 1331, 1313, 1208, 1129, 1041 1 H NMR (300 MHz, CDCl3) δ (ppm): 9.44 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.71 -7.66 (m, 1H), 7.32 (t, J = 7.0 Hz, 1H), 6.98 -6.93 (m, 2H), 5.97 (s, 1H), 5.82 (s, 1H) 13. C{1H} NMR (75 MHz, J = 6.8 Hz, 1H), 7.87(d, J = 8.9 Hz, 1H), 1H), 4H), (m, 4H), 7.34(d, J = 7.6 Hz, 1H), 7.30 (d, J = 6.9 Hz, 1H),6.08 (s, 1H), 5.78 (s, 1H).…”