ABSTRACT
A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.
Subject(s)
Antineoplastic Agents , Quinolines , Cell Line, Tumor , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Humans , Hydroxamic Acids/pharmacology , Polymerization , Quinolines/pharmacology , Repressor Proteins , Tubulin/metabolismABSTRACT
The first total synthesis of the natural product Isoginkgetin as well as four water-soluble Isoginkgetin-phosphate analogues is reported herein. Moreover, the full study of the IP2 phosphate analogue with respect to pharmacological properties (metabolic and plasmatic stabilities, pharmacokinetic, off-target, etc.) as well as in vitro and in vivo biological activities are disclosed herein.
Subject(s)
Biflavonoids , Spliceosomes , Biflavonoids/pharmacology , Phosphates , WaterABSTRACT
The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented on MHC-I molecules. We demonstrated that the splicing inhibitor isoginkgetin and its water-soluble and non-toxic derivative IP2 act at the production stage of the pioneer translation products (PTPs). We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and impairs tumor growth in vivo. IP2 action is long-lasting and dependent on the CD8+ T cell response against TAs. We observed that the antigen repertoire displayed on MHC-I molecules at the surface of MCA205 fibrosarcoma is modified upon treatment with IP2. In particular, IP2 enhances the presentation of an exon-derived epitope from the tumor suppressor nischarin. The combination of IP2 with a peptide vaccine targeting the nischarin-derived epitope showed a synergistic antitumor effect in vivo. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies.
Subject(s)
Adaptive Immunity/drug effects , Antigens, Neoplasm/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Biflavonoids/pharmacology , Cancer Vaccines/pharmacology , Fibrosarcoma/drug therapy , Lymphocytes, Tumor-Infiltrating/drug effects , T-Lymphocytes/drug effects , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Fibrosarcoma/immunology , Fibrosarcoma/metabolism , Fibrosarcoma/pathology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Imidazoline Receptors/immunology , Imidazoline Receptors/metabolism , Lymphocyte Activation/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Mice, Inbred C57BL , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Burden/drug effects , Tumor MicroenvironmentABSTRACT
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.
ABSTRACT
Potent anticancer 4-arylchromene agents 6, as restricted isoCA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substituted 4-chromanones 10 in a one pot procedure which include regioselective arylalkynols hydration, alcohol etherification, MOM-cleavage, and cyclization. Further palladium coupling reactions, using aryl halides and N-tosylhydrazones 11 gave access to a small library of functionalized 4-arylchromenes 6 with good yields. From this series of 4-arylchromenes, we have identified compound 6s which inhibit tubulin assembly at a micromolar level and demonstrate a remarkable nanomolar level of cytotoxicity against four human cancer cell lines. Docking studies showed that isoCA-4 and its restricted chromene analogue 6s adopt a similar positioning in the colchicine binding-site of tubulin.
