Synthesis and Structure–Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4

Abstract

A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.

Combretastatins: More Than Just Vascular Targeting Agents?

“…Furthermore, in this study, CA-4P inhibited sprout formation at concentrations that did not inhibit the proliferation of endothelial cells, confirming direct antiangiogenic properties of CA-4P. Similarly, modulation of endothelial cells by combretastatin analogs has been reported in vitro (Dupeyre et al, 2006;Kong et al, 2010;Romagnoli et al, 2010;Sanna et al, 2010;Arthuis et al, 2011;Porcù et al, 2013) and in vivo (Fortin et al, 2011;Porcù et al, 2013;Zheng et al, 2014). The molecular mechanism of the antiangiogenic properties of TR-644 CA-4 analog was linked to the inhibition of vascular endothelial growth factor-induced phosphorylation of VE-cadherin (Porcù et al, 2013).…”

Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted iso combretastatin A-4 analogs

“…Several reviews outlined this vast array of chemistry focusing on the stabilization of the two aryl rings of CA-4 using one to three atom bridgeheads. [15][16][17][18][19][20] <Figure 1> Figure 1. Representative inhibitors of tubulin polymerization and rational drug design from CA-4 and isoCA-4 to dihydrobenzoxepin analogues 6.…”

Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold

“…This scaffold has also been successfully incorporated into drugs for cancer treatment; in tyrosine kinase inhibitors; and is found in natural products, such as in the welwitindolinone alkaloids . In addition, this motif has been used to conformationally lock biologically active molecules in the form of spirocycles …”

“…[42] In addition, this motif hasb een used to conformationally lock biologically active molecules in the form of spirocycles. [43] Four 2-indolinone derivativesw ere designed, with terminal ortho-tolyl ((AE)-19), 3-pyridyl ((AE)-20), 4-pyridyl ((AE)-21), and aryl sulfonamide ((AE)-22)r ings (Table 1). MOLOCm odeling of the SHMT-bound 3-pyridyl analogue, (+ +)-20,s uggested that two favorable hydrogen-bonding interactions could be formed through the 2-indolinone motif of (+ +)-20 with the side chain of Asn354 and the backboneC =Oo fL ys355 (Supporting Information, SectionS4, Figure S10).…”