Novel 3‑Substituted 7‑Phenylpyrrolo[3,2‑<i>f</i>]quinolin-9(6<i>H</i>)‑ones as Single Entities with Multitarget Antiproliferative Activity

A series of chemically modified 7-phenylpyrrolo­[3,2-<i>f</i>]­quinolinones was synthesized and evaluated as anticancer agents. Among them, the most cytotoxic (subnanomolar GI₅₀ values) amidic derivative <b>5f</b> was shown to act as an inhibitor of tubulin polymerization (IC₅₀, 0.99 μM) by binding to the colchicine site with high affinity. Moreover, <b>5f</b> induced cell cycle arrest in the G2/M phase of the cell cycle in a concentration dependent manner, followed by caspase-dependent apoptotic cell death. Compound <b>5f</b> also showed lower toxicity in nontumoral cells, suggesting selectivity toward cancer cells. Additional experiments revealed that <b>5f</b> inhibited the enzymatic activity of multiple kinases, including AURKA, FLT3, GSK3A, MAP3K, MEK, RSK2, RSK4, PLK4, ULK1, and JAK1. Computational studies showed that <b>5f</b> can be properly accommodated in the colchicine binding site of tubulin as well as in the ATP binding clefts of all examined kinases. Our data indicate that the excellent antiproliferative profile of <b>5f</b> may be derived from its interactions with multiple cellular targets

Design, Synthesis, and Structure–Activity Relationships of Azolylmethylpyrroloquinolines as Nonsteroidal Aromatase Inhibitors

A small library of both [2,3-<i>h</i>] and [3,2-<i>f</i>] novel pyrroloquinolines equipped with an azolylmethyl group was designed and synthesized as nonsteroidal CYP19 aromatase inhibitors. The results showed that azolylmethyl derivatives <b>11</b>, <b>13</b>, <b>14</b>, <b>21</b>, and <b>22</b> exhibited an inhibitory potency on aromatase comparable to that of letrozole chosen as a reference compound. When assayed on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase), compound <b>22</b> was found to be the best and most selective CYP19 inhibitor of them all. In a panel of nine human cancer cell lines, all compounds were either slightly cytotoxic or not at all. Docking simulations were carried out to inspect crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding, and heme iron coordination. This study, along with the prediction of the pharmacokinetics of compounds <b>11</b>, <b>13</b>, <b>14</b>, <b>21</b>, and <b>22</b>, demonstrates that the pyrroloquinoline scaffold represents a starting point for the development of new pyrroloquinoline-based aromatase inhibitors

Synthesis and Biological Evaluation of 2‑(Alkoxycarbonyl)-3-Anilinobenzo[<i>b</i>]thiophenes and Thieno[2,3‑<i>b</i>]pyridines as New Potent Anticancer Agents

Two new series of inhibitors of tubulin polymerization based on the 2-(alkoxycarbonyl)-3-(3′,4′,5′-trimethoxyanilino)­benzo­[<i>b</i>]­thiophene and thieno­[2,3-<i>b</i>]­pyridine molecular skeletons were synthesized and evaluated for antiproliferative activity on a panel of cancer cell lines, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. Antiproliferative activity was strongly dependent on the position of the methyl group on the benzene portion of the benzo­[<i>b</i>]­thiophene nucleus, with the greatest activity observed when the methyl was located at the C-6 position. Also, in the smaller thieno­[2,3-<i>b</i>]­pyridine series, the introduction of the methyl group at the C-6 position resulted in improvement of antiproliferative activity to the nanomolar level. The most active compounds (<b>4i</b> and <b>4n</b>) did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. Compound <b>4i</b> significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice

Concise Synthesis and Biological Evaluation of 2‑Aroyl-5-Amino Benzo[<i>b</i>]thiophene Derivatives As a Novel Class of Potent Antimitotic Agents

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3′,4′,5′-trimethoxybenzoyl)-5-aminobenzo­[<i>b</i>]­thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo­[<i>b</i>]­thiophene was important for maximal antiproliferative activity. Structure–activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds <b>3c</b>–<b>e</b> showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC₅₀ values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound <b>3c</b> (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice