Tiron and trolox potentiate the autophagic cell death induced by magnolol analog Ery5 by activation of Bax in HL-60 cells.

This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.

Studies on novel 4beta-[(4-substituted)-1,2,3-triazol-1-yl] podophyllotoxins as potential anticancer agents.

A series of 4beta-[(4-substituted)-1,2,3-triazol-1-yl] podophyllotoxin congeners have been designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed 1,3-dipolar cycloaddition reaction of C4beta-azido podophyllotoxin and C4beta-azido-4'-O-demethyl podophyllotoxin with N-prop-2-yn-1-ylanilines. These compounds were evaluated for anticancer activity against a panel of seven human cancer cell lines. It was interesting to note that all the compounds exhibited promising activity especially against SF-295 (CNS), HCT-15 (colon) and 502713 (colon) cell lines. Compound 11e was found to be the most promising in this study.

A novel domino-click approach for the synthesis of sugar based unsymmetrical bis-1,2,3-triazoles.

Aryl or sugar azides were treated with allenylmagnesium bromide to generate 1,5-disubstituted-butynyl-N-aryl or N-glycosyl-1,2,3-bistriazoles in a domino fashion. Upon Cu(I) catalyzed 1,3-dipolar cycloaddition with sugar azides, these compounds afford novel unsymmetrical bis-1,2,3-triazoles in high yields.

4ß-amidotriazole linked podophyllotoxin congeners: DNA topoisomerase-IIα inhibition and potential anticancer agents for prostate cancer.

Topoisomerases (topo-I and topo-II) have occupied a significant role in DNA replication, transcription, and are a promising set of antitumor targets. In the present approach, a series of new 4ß-amidotriazole linked podophyllotoxin derivatives (10a-i and 11a-k) were designed, synthesized by employing the click chemistry and their biological activities were evaluated. The majority of derivatives showed promising antiproliferative activity with IC50 values ranging from 1 to 10 µM on the six human cancer cell lines; cervical (HeLa), breast (MCF-7), prostate (DU-145), lung (A549), liver (HepG2) and colon (HT-29). Among them, some of the congeners 10b, 10g and 10i have shown remarkable cytotoxicity with IC50 values of, < 1 µM against the tested cancer cell lines and found to be more active than etoposide. Topoisomerase-mediated DNA relaxation assay results showed that the derivatives could efficiently inhibit the activity of topoisomerase-II. In addition, flow cytometry analysis on DU-145 cells revealed that these compounds arrest G2/M phase of cell cycle. Further apoptotic studies were also performed on these DU-145 cells, which showed that this class of compounds could induce apoptosis effectively.

Synthesis and anticancer activity of novel spiro-isoxazoline and spiro-isoxazolidine derivatives of α-santonin.

In the present study, novel spiro derivatives of α-santonin were prepared and tested for their anticancer activity against a panel of six human cancer cell lines. Spiro-isoxazoline and spiro-isoxazolidine derivatives have been generated on C-ring of α-santonin (α-methylene-γ-butyrolactone) by the 1,3-dipolar cycloaddition of α-santonin derivative 6 with nitrile oxides 7 and nitrones 9 respectively. Among all, compound 10b″ had shown IC50 of 0.01, 0.5 and 0.3 µM against PC-3, THP-1 and MCF-7 cell lines respectively. Further, flow cytometry studies showed that PC-3 cells treated with the spiro-isoxazolidine derivative 10b″ were arrested in the sub G1 phase of the cell cycle in a concentration dependent manner. The spiro-isoxazolidine derivative 10b″ also showed concentration dependent inhibitory activity against NF-κB, p65 with 57% inhibition in 24 h at 10 µM.

Design and synthesis of novel magnolol derivatives as potential antimicrobial and antiproliferative compounds.

A series of novel magnolol derivatives were synthesised and evaluated for in vitro antimicrobial and antiproliferative activities. We found that most of the compounds were effective inhibitors of Staphylococcus aureus, MRSA and VRE with MIC in the range of 1-64 µg/mL and MBC in the range of 1-128 µg/mL. Few derivatives also exhibited promising antifungal activity. Some magnolol analogues exhibited promising antiproliferative activity than parent magnolol when tested against three human cancer cell lines.

Study of the adjuvanticity of lysine lipopeptides; carbamate analogs elicit strong Th1 and Th2 response to ovalbumin in mice.

Bacterial lipoproteins and their synthetic analogs are strong immune modulators of the early host responses. In view of the strong adjuvanticity of bacterial lipopeptide mimics bearing lysine residues, a focused library of lipidated dipeptides and tripeptides has been synthesized with a view to understand the pattern of activity vis a vis the site and extent of lipidation. Compounds 4, 5 and 14 stimulate OVA specific IgG titer, neutralization of antibodies (IgG1 and IgG2a), T lymphocyte sub-sets (CD4/CD8) and its production of soluble mediators for Th1 (IFN-γ)/Th2 (IL-4) cytokines and costimulatory molecules (CD80/CD86) which are ideal traits of immune adjuvants. The results support lipidated lysine dipeptides as potent enhancers of humoral and cell mediated immune responses and thus might become promising immune-adjuvants for self adjuvanted vaccines.

D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: Synthesis and biological evaluation.

A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the 'click chemistry' approach. These derivatives were screened for their anticancer activity against seven human cancer cell lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with compound 5e as the most active in this study.

Studies on novel D-ring substituted steroidal pyrazolines as potential anticancer agents.

An efficient and facile synthesis of 17-pyrazolinyl derivatives of pregnenolone and their evaluation as potential anticancer agents against various human cancer cell lines are reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to the corresponding benzylidine derivatives and finally the conversion of this derivative to the stable steroidal 17-pyrazoline. Various compounds 4b, 4c, 4e, 4f, 4h and 4j showed significant cytotoxic activity especially against HT-29, HCT-15, 502713 cell lines.

Development of novel lipidated analogs of picroside as vaccine adjuvants: acylated analogs of picroside-II elicit strong Th1 and Th2 response to ovalbumin in mice.

The acylated analogs of picroside-II were synthesized and tested for immune-adjuvant activity in the presence of weak antigen ovalbumin found to stimulate anti-OVA IgG titer, neutralizing antibody (IgG1 and IgG2a) titer as well as the production of soluble mediators of a Th1 response (IL-2 and IFN-γ) and Th2 response (IL-4) and proliferation of T lymphocytes sub-sets (CD4/CD8). Furthermore, these modified analogs of picroside-II were able to elicit a substantial increase in anti-OVA IgG when compared with OVA alone. These results support the use of acylated analogs particularly PK-II-3 and PK-II-4 as potent enhancer of antigen-specific Th1 and Th2 immune responses and thus are promising immune-adjuvant candidate for vaccines.