ABSTRACT
In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC50 value of 1â µM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5â nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Oxazepines/pharmacology , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aza Compounds/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Oxazepines/chemical synthesis , Oxazepines/chemistry , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tumor Cells, CulturedABSTRACT
The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are described. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity. We have also showed that a carbazole or an indole nucleus are very effective as B-rings in this series, leading to anti-cancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50â¯=â¯70 pM against HCT116â¯cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level. Moreover, at a concentration of 5â¯nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116â¯cells. It was also showed that after few hours 1a at a concentration of 10â¯nM totally disrupted endothelial network formation on Matrigel.
Subject(s)
Antineoplastic Agents/pharmacology , Cytotoxins/pharmacology , Methylamines/pharmacology , Mitosis/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Methylamines/chemical synthesis , Methylamines/chemistry , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
An unexpected ring opening of 3-aminobenzofurans promoted by NaO tBu in hot toluene, leading to a variety of α-ketoimines, is described. In the presence of 3-iodobenzofurans, NaO tBu mediates the 3-aminobenzofurans ring opening via a possible radical pathway without the help of any external radical sources.
ABSTRACT
We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure-activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.
Subject(s)
Carbazoles/pharmacology , Quinaldines/pharmacology , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Carbazoles/chemical synthesis , Carbazoles/metabolism , Cell Line, Tumor , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Microsomes, Liver/metabolism , Molecular Structure , Polymerization/drug effects , Protein Binding , Quinaldines/chemical synthesis , Quinaldines/metabolism , Rats , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/metabolismABSTRACT
The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50 < 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as B-ring, led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.
Subject(s)
Drug Design , Protein Multimerization/drug effects , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Tubulin/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , M Phase Cell Cycle Checkpoints/drug effects , Molecular Docking Simulation , Protein Structure, Quaternary , Quinazolines/chemistry , Quinazolines/metabolism , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/metabolismABSTRACT
For the first time, the combination of chlorotrimethylsilane with NaI is used as a selective reducting system toward 1,2-diketones. This combination is successfully evaluated with several unsymmetrically benzil derivatives, which are reduced in good yields and with a total α-regioselectivity at room temperature. Identification of benzoin intermediates is achieved, and a mechanistic radical process is proposed.
