ABSTRACT
This review brings together the various pathways to the oxazino[4,3-a]indole motif over the last decades. Representative examples showing the scope of these processes will illustrate the synthetic pathways and the biological activity of the synthesized oxazinoindoles will be mentioned wherever possible.
Subject(s)
Indoles/chemical synthesis , Humans , Molecular Structure , StereoisomerismABSTRACT
In this study, a variety of original ligands related to Combretastatin A-4 and isoCombretastatin A-4, able to inhibit the tubulin polymerization into microtubules, was designed, synthesized, and evaluated. Our lead compound 15d having a quinazoline as A-ring and a 2-substituted indole as B-ring separated by a N-methyl linker displayed a remarkable sub-nanomolar level of cytotoxicity (IC50 < 1 nM) against 9 human cancer cell lines.
Subject(s)
Antineoplastic Agents/pharmacology , Indoles/chemistry , Stilbenes/chemistry , Tubulin Modulators/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Drug Stability , Humans , Indoles/metabolism , Indoles/pharmacology , Microsomes, Liver/metabolism , Molecular Docking Simulation , Rats , Stilbenes/metabolism , Stilbenes/pharmacology , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacologyABSTRACT
In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6 nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5- and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both in vitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562 cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.
Subject(s)
Drug Design , Stilbenes/chemistry , Stilbenes/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclization , Humans , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Stilbenes/chemical synthesis , Tubulin/metabolism , Tubulin Modulators/chemical synthesisABSTRACT
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
Nanoformulated calix[8]arenes functionalized with N-heterocyclic carbene (NHC)-palladium complexes were found to be efficient nano-reactors for Suzuki-Miyaura cross-coupling reactions of water soluble iodo- and bromoaryl compounds with cyclic triol arylborates at low temperature in water without any organic co-solvent. Combined with an improved one-step synthesis of triol arylborates from boronic acid, this remarkably efficient new tool provided a variety of 4'-arylated phenylalanines and tyrosines in good yields at low catalyst loading with a wide functional group tolerance.
Subject(s)
Amino Acids/chemistry , Calixarenes/chemistry , Nanoparticles/chemistry , Palladium/chemistry , Water/chemistry , CatalysisABSTRACT
We have developed new benign palladium nanoparticles able to catalyze the Suzuki-Miyaura cross-coupling reaction on human thyroglobulin (Tg), a naturally iodinated protein produced by the thyroid gland, in homogenates from patients' tissues. This represents the first example of a chemoselective native protein modification using transition metal nanoobjects in near-organ medium.
