Imparting aromaticity to 2-pyridone derivatives by O-alkylation resulted in new competitive and non-competitive PIM-1 kinase inhibitors with caspase-activated apoptosis.

New aromatic O-alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. 4c and 4f showed potent in vitro anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, 4c and 4f induced apoptosis in the four tested cancer cell lines with high percentage. In addition, 4c and 4f significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 4c and 4f showed potent PIM-1 kinase inhibitory activity with IC50 = 0.110, 0.095 µM, respectively. Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities.

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver-Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases.

Zika M Oligopeptide ZAMP Confers Cell Death-Promoting Capability to a Soluble Tumor-Associated Antigen through Caspase-3/7 Activation.

Mosquito-borne Zika virus (ZIKV) is an emerging flavivirus of medical concern associated with neurological disorders. ZIKV utilizes apoptosis as a mechanism of cell killing. The structural M protein may play a role in flavivirus-induced apoptosis. The death-promoting capability of M has been restricted to an oligopeptide representing the residues M-32/40. Here, we evaluated the apoptosis inducing ability of the residues M-31/41 of ZIKV. The ZIKV M oligopeptide was associated to a soluble form of GFP (sGFP) and the resulting sGFP-M31/41 construct was assessed in Huh7 cells. Expression of sGFP-M31/41 can trigger apoptosis in Huh7 cells through caspase-3/7 activation. The translocation of sGFP-M31/41 in the endoplasmic reticulum was a prerequisite for apoptosis induction. The residues M-33/35/38 may play a critical role in the death-promoting activity of sGFP-M31/41. The effect of ZIKV M oligopeptide defined as ZAMP (for Zika Apoptosis M Peptide) on expression of a tumor-associated antigen was assayed on megakaryocyte-potentiating factor (MPF). Expression of MPF-ZAMP construct resulted in caspase-associated apoptosis activation in A549 and Huh7 cells. ZIKV has been proposed as an oncolytic virus for cancer therapy. The ability of the Zika M oligopeptide to confer death-promoting capability to MPF opens up attractive perspectives for ZAMP as an innovative anticancer agent.

ONS-donor ligand based Pt(II) complexes display extremely high anticancer potency through autophagic cell death pathway.

The current study unveils ONS-donor ligand based Pt(II) complexes with unusual anticancer potency showing higher anticancer effect as compared to cisplatin. This series of Pt(II)(R-salicylaldimine)Cl (C1a-C4a) (R = 5-H, 5-CH3, F, 3-CH3O) complexes were prepared in single step in good isolated yields from commercially available materials. The chloride ancillary ligand of "a" series (C1a-C4a) was replaced with 4-picoline and "b" series of four complexes Pt(II)(R-salicylaldimine)(4-picoline)BF4 (C1b-C4b) (R = 5-H, 5-CH3, F, 3-CH3O) was obtained. All these complexes were characterized by different structure elucidation techniques. Among these, the structures of C1a, C2a, C2b and C3b were determined in solid state by single crystal X-ray analysis. We found quick aquation of "a" series of complexes in DMSO/water mixture that was well investigated by 1H NMNR, LCMS and ESI-MS, while "b" series of these complexes was quite stable over a month as described by the 1H NMNR in DMSO/D2O mixture. This ONS-donor ligand based class of Pt(II) complexes showed unusual anticancer potency in non-small cell lung cancer A549, colorectal cancer HT-29 and triple negative breast cancer MDA-MB-231 cells. These Pt(II) complexes induced PARP cleavage and significantly inhibited colony formation ability of cancer cells. Mechanistically, we found reduced aggressive growth of cancer cells by the induction of autophagic cell death via LC3-I/LC3-II expression and recruitment of LC3B to autophagosomal membrane. These complexes induced p21 expression, that suggested their potentials to suppress cell cycle progression. Significant activation of Caspase3/7-dependent apoptotic signaling was observed in cancer cells treated with these Pt(II) complexes. Morphological changes of cancer cells suggested their potentials to modulate epithelial-mesenchymal-transition (EMT) like features of cancer cells. Gel electrophoresis study revealed their interaction with plasmid DNA. Similarly, strong growth retardation effect and filamentous morphology was observed in Escherichia coli (E. coli). These ONS-donor Pt(II) complexes possessed strong anticancer effect in multiple human cancer cells via activation of multiple pathways for apoptotic and autophagic cell death.

Glycosmis pentaphylla (Retz.) DC arrests cell cycle and induces apoptosis via caspase-3/7 activation in breast cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycosmis pentaphylla (Retz.) DC belonging to the family Rutaceae has been traditionally used for the treatment of rheumatism, anaemia, jaundice, skin diseases, bronchitis etc. The plant is traditionally considered as anti-cancer medicine and used by the healers of Bangladesh to treat all types of cancers. Perhaps the key to many of its medicinal applications is its inherent anti-inflammatory property. AIM OF THE STUDY: The present study is aimed at evaluating the effect of various fractions of G. pentaphylla (Retz.) DC leaves on the cell cycle and apoptosis of breast cancer cells viz. MCF-7 and MDA-MB-231. MATERIALS AND METHODS: Various extracts and fractions of the leaves of G. pentaphylla (Retz.) DC were studied for their cytotoxicity with the help of Sulforhodamine B assay, in MCF-7, MDA-MB-231 and Vero cell lines. The most active fractions were studied for their effect on the cell cycle of MCF-7 and MDA-MB-231 cells. Apoptotic studies were done using Hoechst staining, DNA fragmentation, Annexin V staining and caspase-3/7 activation assay in breast cancer cells. HPLC and HPTLC profiling of the active fractions were done. RESULTS: HPTLC and HPLC profiling revealed the presence of lupeol, chrysin, quercetin, ß-sitosterol and kaempferol as components in active fractions. Lupeol and chrysin are being reported in this plant for the first time. The studies showed that the selected fractions possess cell cycle inhibitory and apoptosis inducing effect on both MCF-7 and MDA-MB-231 cells. Apoptotic effect of the fractions on MCF-7 and MDA-MB-231 cells may be through the mitochondrial pathway by the activation of caspase-3/7.