Mannich Bases: Centrality in Cytotoxic Drug Design.

Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic, and prodrugs classes, and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines, and promising leads for future drug development have also been discussed. Structure-activity relationships, along with the targets on which these cytotoxic Mannich bases act, have been included as well.

1, 2-Dihexadecanoyl-sn-glycero-3-phosphoethanolamin (DPPE), doxorubicin and folic acid conjugated micelles for cancer management in tumor bearing BALB/c mice.

Aim of the present investigation was to assess and compare the in-vitro and in-vivo cancer targeting propensity of DPPE-FA-DOX Micelles and free DOX in tumor bearing BALB/c mice. The DOX was conjugated with 1, 2-Dihexadecanoyl-sn-glycero-3-phosphoethanolamin (DPPE) and folic acid using Di-cyclohexyl-carbodiimide, confirmed by Fourier transform infrared spectroscopy (FTIR) and proton NMR. DPPE-FA-DOX micelles were prepared using thin film method and evaluated for zeta potential, particle size, surface morphology, in- vitro drug release study etc. In-vitro anticancer activity and apoptosis assay was evaluated in breast cancer (MCF-7) cells using MTT assay and flow cytometer respectively. In-vivo biodistribution and toxicity assessment were evaluated in rats whereas antitumor activity in tumor bearing BALB/c mice. Prepared micelles were spherical with size and zeta potential of 295.6 + 84.4 nm and 0.8 ± 0.24 mV respectively. Apoptosis assay for DPPE-FA-DOX micelles treated cells using Annexin V/PI staining demonstrated 56.2% apoptotic cells. Remarkably, DPPE-FA-DOX micelles improved DOX bioavailability by 7 fold and diminished plasma elimination with no sign of tissue toxicity compared to free DOX. In-vivo biodistribution studies revealed that micelles facilitated higher accumulation of DOX in tumor than free DOX. DPPE-FA-DOX micelles treated mice survived for 62 days than Free DOX (40 days), revealed by Kaplan-Meier survival curve analysis. Histopathological examination of liver, kidney and heart tissues of micelles treated rat's corroborated reduced systemic toxicity than free DOX. Conclusively, DPPE-FA-DOX micelles could potentially facilitate the targeted delivery of DOX to tumors.