Tyrosine-Derived Novel Benzoxazine Active in a Rat Syngenic Mammary Tumor Model of Breast Cancer.

In continuing efforts of improving benzoxazepine derivatives as an anti-breast cancer agent, a new chemical entity, benzoxazine, was designed from scaffold morphing. Structure-activity relationship studies revealed that H, -OMe, -CF3, and -F were well tolerated on R1 and R2 positions of ring A, and R2 as -CH2CH2N(CH2)4 (N-ethyl pyrrolidine) and -CH2CH2N(CH2)5 (N-ethyl piperidine) chains on ring D increased activities (Series B, Figure 3). 13d selected as a lead compound (IC50: 0.20 to 0.65 µM) induces apoptosis, cell cycle arrest, and loss of mitochondrial membrane potential in breast cancer cells. Compound 13d was formulated into 13d-f using cyclodextrin to improve its solubility for a pharmacokinetic, in vivo efficacy study. Both 13d and 13d-f regressed tumor growth at concentrations of 5 and 20 mg/kg better than tamoxifen without any mortality in a rat syngenic mammary tumor model. Collectively, our data suggest that tyrosine-derived novel benzoxazine 13d could be a potential lead for the treatment of breast cancer and hence deserve further in-depth studies.

New Spisulosine Derivative promotes robust autophagic response to cancer cells.

Therapy resistance by evasion of apoptosis is one of the hallmarks of human cancer. Therefore, restoration of cell death by non-apoptotic mechanisms is critical to successfully overcome therapy resistance in cancer. By rational drug design approach, here we try to provide evidence that subtle changes in the chemical structure of spisulosine completely switched its cytotoxic function from apoptosis to autophagy. Our most potent molecule (26b) in a series of 16 synthesized derivatives showed robust autophagic cell death in diverse cancer cells sparing normal counterpart. Compound 26b mediated lethal autophagy induction was confirmed by formation of characteristic autophagic vacuoles, LC3 puncta formation, upregulation of signature autophagy markers like Beclin and Atg family proteins. Altogether, we have detected novel autophagy inducer small molecule which can be tested further for drug discovery research.

Targeting progesterone metabolism in breast cancer with l-proline derived new 14-azasteroids.

Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.