An efficient and facile green synthesis of bisindole methanes as potential Mtb FtsZ inhibitors.

The rising multidrug-resistant Mycobacterium tuberculosis (Mtb) strain made current anti-TB drug therapy ineffective and became a major health concern globally; hence it is crucial to develop new molecules against vital targets with a novel mechanism. Mtb Filamenting temperature sensitive protein Z (FtsZ), a tubulin homolog plays a major role in bacterial cell division, in the presence of GTP recruiting essential proteins for cell division and considered to be a potential target for drug discovery. Most of MtbFtsZ inhibitors known are of antibiotics from natural resources and suffer from cellular uptake, specificity. In the present study, we demonstrated for the first time bisindole derivatives as potential MtbFtsZ inhibitors. The synthesis of bisindole derivatives has been carried out using green synthetic approach by applying ammonium molybdate as a catalyst under Ultrasonic condition. Among the synthesized bisindole derivative, I16 and I5 showed 62.29% and 56.86% inhibition of GTPase activity of MtbFtsZ and increased the length of Mycobacterium smegmatis and Bacillus subtilis by two folds. Further compound I16 inhibited Mtb growth with a MIC of 37.5 µg/ml. To explain these interactions, detailed Molecular docking studies have been carried out and found to be supportive to the biological activity.

Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies.

A new scaffold N-(9-(ortho/meta/para-(benzyloxy)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl) isonicotinamide (H1-3) was discovered as a hSIRT1 inhibitor through virtual screening of in-house database. Based on these hits, a library of compounds were designed, synthesized and tested for in vitro hSIRT1 activity. The most potent compound 4d in the series showed a significant inhibition of SIRT1 activity. Further antitumor studies of compound 4d, showed a dose dependent increase in acetylation of p53K382 and decrease in SIRT1 with an IC(50) of 0.25 µM in MDA-MB231 breast cancer cell lines. Individual 3D-QSAR analysis using Schrödinger showed distribution of hydrophobic and non polar positive co-efficient at ortho position essential for bioactivity based on 4d.

Anticancer activity of Pupalia lappacea on chronic myeloid leukemia K562 cells.

BACKGROUND: Cancer is one of the most prominent human diseases which has enthused scientific and commercial interest in the discovery of newer anticancer agents from natural sources. Here we demonstrated the anticancer activity of ethanolic extract of aerial parts of Pupalia lappacea (L) Juss (Amaranthaceae) (EAPL) on Chronic Myeloid Leukemia K562 cells. METHODS: Antiproliferative activity of EAPL was determined by MTT assay using carvacrol as a positive control. Induction of apoptosis was studied by annexin V, mitochondrial membrane potential, caspase activation and cell cycle analysis using flow cytometer and modulation in protein levels of p53, PCNA, Bax and Bcl2 ratio, cytochrome c and cleavage of PARP were studied by Western blot analysis. The standardization of the extract was performed through reverse phase-HPLC using Rutin as biomarker. RESULTS: The results showed dose dependent decrease in growth of K562 cells with an IC50 of 40 ± 0.01 µg/ml by EAPL. Induction of apoptosis by EAPL was dose dependent with the activation of p53, inhibition of PCNA, decrease in Bcl2/Bax ratio, decrease in the mitochondrial membrane potential resulting in release of cytochrome c, activation of multicaspase and cleavage of PARP. Further HPLC standardization of EAPL showed presence 0.024% of Rutin. CONCLUSION: Present study significantly demonstrates anticancer activity of EAPL on Chronic Myeloid Leukemia (K562) cells which can lead to potential therapeutic agent in treating cancer. Rutin, a known anti cancer compound is being reported and quantified for the first time from EAPL.

Antiproliferative activity and standardization of Tecomella undulata bark extract on K562 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Tecomella undulata is primarily used in the treatment of syphilis, painful swellings and cancer by traditional healers. Also, it is claimed to be useful in treating urinary discharges, enlargement of spleen, leucorrhoea, leukoderma, tumors, liver disorders, gonorrhea, gout and promotes wound healing in Indian traditional system of medicine. AIM: To establish a scientific validation for the antitumor effects of Tecomella undulata bark and explore the mechanistic pathway in chronic myeloid leukemia cell line, K562. The study was further extended to standardize the extract using quercetin as biomarker. METHODS: Induction of apoptosis by chloroform extract of Tecomella undulata bark (CTUB) was determined by MTT, Annexin V and caspase activation assays. The cell cycle analysis was done by flow cytometer and nuclear staining by DAPI. The standardization of the extract was performed through reverse phase-HPLC method under PDA detection. RESULT: Results clearly showed the induction of apoptosis by CTUB in K562 cells. The effect was found to be dose dependent, having IC(50) of 30 µg/ml with activation of FAS, FADD, caspase 8, caspase 3/7 and fragmentation of DNA. The bioactive CTUB was determined to possess 0.03% (w/w) of quercetin. CONCLUSION: The investigation clearly demonstrated the potential antitumor effect of CTUB, thereby validating the traditional claim. Quercetin, known to have anticancer activity is being reported and quantified for the first time from the bark of Tecomella undulata.