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