Synthesis and evaluation of tetrahydropyrrolo[1,2-]quinolin-1(2)-ones as new tubulin polymerization inhibitors.

Here we explored new 1,5-disubstituted pyrrolidin-2-ones 1, 2 and 5-aryl-3,3,4,5-tetrahydropyrrolo[1,2-]quinoline-1(2)-ones 3 as inhibitors of tubulin polymerization. We evaluated their effects on microtubule dynamics and on the proliferation of A549 cells, using flow cytometry-based cell cycle analysis. The results were verified with phase-contrast microscopy in three cancer cell lines: A549, HeLa and MCF-7.

Microtubule rescue control by drugs and MAPs examined with in vitro pedestal assay.

Microtubules are essential cytoskeletal polymers, which exhibit stochastic transitions between assembly and disassembly, known as catastrophes and rescues. Understanding of catastrophes, rescues, and their control by drugs and microtubule associated proteins (MAPs) has been informed by in vitro reconstitutions of microtubule dynamics. In such experiments microtubules are typically observed on a flat surface of the coverslip.

Theory of tip structure-dependent microtubule catastrophes and damage-induced microtubule rescues.

Microtubules are essential cytoskeletal polymers that exhibit stochastic switches between tubulin assembly and disassembly. Here, we examine possible mechanisms for these switches, called catastrophes and rescues. We formulate a four-state Monte Carlo model, explicitly considering two biochemical and two conformational states of tubulin, based on a recently conceived view of microtubule assembly with flared ends.

Expanding Stereoelectronic Limits of - Cyclizations: Synthesis of Benz[]azepines from Donor-Acceptor Cyclopropanes.

The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in -- cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of - cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-- process. Substrates containing a -alkyl--arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[]azepin-2-ones in high yields.