Synthesis of Combretastatin A-4 and 3′-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression

Abstract

Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3′-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549 cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the parent compound.

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

“…G 2 /M phase cell cycle arrest is strongly associated with tubulin polymerization inhibition and is well established that CA-4 causes cell cycle arrest at G2/M phase [ 28 , 29 , 30 ]. The excellent potency of compound 19h with respect to inhibition of MCF-7 cell proliferation prompted further investigation us on whether the activity of 19h was due to cell cycle arrest.…”

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…As such, several VDAs have been tested in combination with additional therapies [ 11 , 41 ], including radiotherapy [ 41 , 42 , 43 , 44 , 45 , 46 ], antiangiogenic agents (such as bevacizumab) [ 47 , 48 ], traditional cytotoxic chemotherapy (e.g., carboplatin, paclitaxel) [ 41 , 49 , 50 , 51 , 52 , 53 , 54 ] and recently immunotherapy [ 55 , 56 ]. There is a current resurgence of interest in VDAs and frequent reports describe novel agents, many based on the colchicine/combretastatin motif [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] ( Figure 2 A). These molecules are typically hydrophobic and are modified as phosphate prodrugs to enhance aqueous solubility and allow ease of delivery.…”

Design, Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives

“…It is well known that CA-4 as microtubule-targeting agent modify the tubulin-microtubule equilibrium and thus challenge the development of the mitotic spindles throughout the M phase, causing cell cycle arrest at G 2 /M phase and eventually prompt apoptosis [ 12 , 47 , 48 ]. The effect of the functioning compound benzotriazole analogue BI9 at concentration 1 µM on the leukemia HL-60 cells was evaluated by flow cytometry for 48 and 72 h. As shown in Figure 2 A, Compounds BI9 brought clear G 2 /M arrest at 48 and 72 h with the proportions of HL-60 cells in G 2 /M phase of 32.3% and 35.1%, respectively.…”