Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure

Abstract

Quinazolinone-based anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of steroid sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI 300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.

Modes of cell death induced by tetrahydroisoquinoline-based analogs in MDA-MB-231 breast and A549 lung cancer cell lines

“…STX 3451 has a disruptive effect on both the actin and tubulin cytoskeleton leading to the rounding of cells, fragmentation of chromatin and multilobed nucleoli and actin filament disruption. 21 , 32 During this in vitro study, A549 and MDA-MB-231 cells were exposed to the determined GI 50 values of 2-ME, STX 2895, STX 3329, STX 3451 and STX 3450 for 24 h and thereafter stained with anti-tubulin antibodies. Fluorescent microscopy indicated that the compounds resulted in microtubule abrogation and DNA fragmentation.…”

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

“…The sulfamate group is shown to be a mediator of this affinity with β-tubulin, the first example of a sulfamate ester bound to tubulin. Future studies will potentially involve evaluation of this compound in animal models [83].…”

An Aqueous Facile Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives by Reverse Zinc Oxide Micelles as Nanoreactor

“…N-heterocycles are important integral pharmacophoric units ubiquitously used in a variety of biologically active natural products, agrochemicals, pharmaceutical and synthetic drugs (Khan et al, 2016). 2,3-Dihydroquinazolin-4(1H)-one plays an important role in the aromatic nitrogen-containing heterocycles because of their abundant pharmacological and biological activities (Kshirsagar, 2015;Zawawi et al, 2015;Dohle et al, 2018). Compounds containing this motif have shown significant biological activities which include anticancer, anticonvulsant, antidefibrillatory, analgesic, diuretic, antihistamine, antihypertensive, and many other activities (Patil et al, 2015;Zawawi et al, 2015).…”