Advances in chalcones with anticancer activities.

Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).

4-Amino-2-arylamino-5-indoloyl/cinnamoythiazoles, analogs of topsentin-class of marine alkaloids, induce apoptosis in HeLa cells.

Marine organisms provide several biologically active compounds that include alkaloids with high cytotoxic activity but only a few of them have so far reached clinical stage, due partly to their limited supply and complex structural features. In an attempt to develop novel anticancer compounds, we have now synthesized diaminoindoloylthiazoles (4a-c; DIT1-3) and diaminocinnamoylthiazoles (5a,b; DCT1-2) as analogs based on a topsentin scaffold and investigated the cytotoxic and apoptotic activities of these compounds in HeLa cells. The results suggest that diaminoindoloylthiazoles (DIT1-3) inhibit cell growth and among these, DIT3 is the most cytotoxic against HeLa cells (IC50 1 µM). The diaminocinnamoylthiazoles DCT1 and DCT2, which can be viewed as curcumin-diaminothiazole hybrids, also inhibited cell growth but at relatively higher concentrations with IC50 values of 60 and 30 µM, respectively. These compounds induced apoptosis through the intrinsic pathway by reducing the mitochondrial membrane potential and activating caspases, 9 and 3, but not caspase 8. Among the marine alkaloid analogs tested in this study, DIT1-3 are very effective in inducing apoptosis of HeLa cells followed by DCT2 and DCT1. The treated cells were arrested in G2/M phase followed by accumulation of the cells in the Sub G0 phase. The curcumin-diaminothiazole hybrid DCT1 had the maximum effect in downregulating TNF-induced NF-κB activation among the compounds tested in this study. Thus, we demonstrate that diaminoindoloylthiazoles and diaminocinnamoylthiazoles induce apoptosis, regulate cell cycle and NF-κB signaling and thus show promising anticancer effects that warrant further investigation.

Immune responses generated by intramuscular DNA immunization of Brugia malayi transglutaminase (BmTGA) in mice.

An attempt was made to evaluate the immunoprophylactic efficacy of Brugia malayi transglutaminase (BmTGA) as a DNA vaccine, for human lymphatic filariasis. BmTGA was cloned and characterized in the DNA vaccine vector pVAX1. Further, the tissue distribution study of the DNA construct, pVAX-TGA was carried out in mice and the DNA vaccine was shown to be efficiently distributed to all the organs, was accessible to the immune system, and at the same time was metabolized quickly and did not pose problems of toxicity. Intramuscular immunization in mice showed significant antibody production and splenocyte proliferation upon antigenic stimulation. The immune responses were biased towards the Th1 arm, as evaluated in terms of isotype antibody distribution and cytokine profile. Thus, analysis of the humoral and cellular immune responses indicated that BmTGA is a potent immunogen. However, protection studies as determined by the micropore chamber method using live microfilarial larvae, showed that the DNA vaccine could confer only partial protection in the mouse model. We conclude that despite the induction of sufficient humoral and cellular immune responses, BmTGA as a DNA vaccine could not confer much protection against subsequent challenge and other aspects of the immune responses need to be further investigated.

Evaluation of immunoprophylactic efficacy of Brugia malayi transglutaminase (BmTGA) in single and multiple antigen vaccination with BmALT-2 and BmTPX for human lymphatic filariasis.

An attempt was made to study the immunoprophylactic efficacy of recombinant Brugia malayi transglutaminase (BmTGA) as protein vaccine along with two other recombinant proteins, Brugia malayi abundant larval transcript-2 (BmALT-2) and Brugia malayi thioredoxin peroxidase (BmTPX), in single and multiple antigen form for human lymphatic filariasis. Parasite challenge studies in jirds exhibited protection of 30%, 69%, and 43% against BmTGA, BmALT-2, and BmTPX, respectively, in single antigen vaccination mode. The protective efficacy of BmTGA was enhanced significantly (74%) by immunizing the jirds in multiple antigen vaccination mode along with BmTPX, whereas immunizing with the combination of BmTGA and BmALT2 conferred only 47% protection. The same protection profiles were obtained by in vitro antibody-dependent cellular cytotoxicity, using live microfilariae and L3 stage larvae. The immune response was Th2 biased, irrespective of single or multiple vaccinations. The combination of BmTGA and BmTPX seems to be a promising vaccine candidate against lymphatic filariasis.