Aswini Kumar Giri

Design and synthesis of D-ring steroidal isoxazolines and oxazolines as potential antiproliferative agents against LNCaP, PC-3 and DU-145 cells.

Two series of novel steroidal isoxazolines and oxazolines were synthesized through different routes from dehydroepiandrosterone acetate and pregnenolone acetate, respectively. The synthesis of the analogs of both series is multistep and proceeds in good overall yields. While the key step in the synthesis of former is the cycloaddition of aromatic nitrile oxides across α,β-unsaturated olefins, it is the condensation of α,β-azidoalcohols with aromatic aldehydes in the later. Compounds of both the series were tested for their cytotoxic activities against LNCaP, PC-3 and DU-145 prostate cancer cell lines. Amongst all the compounds of both the series screened for their prostate cancer activity, compound 6a, 6e and 12a are the most active especially against LNCaP and DU-145 cancer cell lines.

Entrap and release of Phe–Phe nanotubes in sol–gel derived silicate matrix: study through nanosilver interaction

After the discovery of the ability of dipeptide self-assembly, numerous research activities have been reported on Phe–Phe dipeptide based nano-materials. However, entrapping peptide nanotubes in a silicate matrix has not been carefully studied. This paper reports on self-assembled Phe–Phe nanotubes entrapped in a silicate matrix derived by a simple, and modified acid mediated sol–gel approach. Here, interaction of silver nanoparticles with regained nanotubes from the silicate matrix is reported. Mass spectrometry data showed the self-assembly of peptide monomers. Scanning electron microscopy and transmission electron microscopy studies have been used to examine the shapes and sizes of the nano-structures, and the results provide a promising method for trapping peptide based nanotubes. UV–Visible spectra suggest that there are some effects of silicate environment around Phe–Phe NTs on its absorbance. Density functional calculations showed the probable type of interaction between peptide and Ag atoms. This study can be useful for future applications, which are based on immobilization strategy for drug carrying and sensing.

Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential

Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding. Complementing our genetic approach, we demonstrate utility of a bivalent pharmacophore with dual activity as a μ/δ opioid agonist and NK1R antagonist in inhibiting nociception in an animal model of acute pain while lacking any positive reinforcement. These data indicate that dual targeting of the dopaminergic reward circuitry and pain pathways with a multifunctional opioid agonist–NK1R antagonist may be an efficacious strategy in developing future analgesics that lack abuse potential.

Design of Multivalent Ligands that Cross the Blood Brain Barrier for the Treatment of Neuropathic Pain Without Toxicities

Pain, especially prolonged and neuropathic, is the most ubiquitous and expensive disease in the U.S. and worldwide and treatments are inadequate or ineffective and often lead to enhanced pain sensitivity, addiction and poor quality of life. New modalities for treatment are urgently needed but are not forthcoming from pharma. We have proposed that a new approach to drug design is needed which takes into account the changes in the expressed genome that accompany these disease states [1]. In particular, in prolonged and neuropathic pain there is up-regulation of neurotransmitters and their receptors in ascending and descending pain pathways that are stimulatory and therefore enhance the pain perception. From these and other findings, we have hypothesized that the design of a multivalent ligand that has agonist activity at the mu and delta opioid receptors (balanced or favoring μ or δ receptors) with antagonist activities at the up-regulated stimulatory receptor (e.g. ligands for neurokinin-1 (NK-1) receptor) all in single ligand, would have potent analgesic activities but without the toxicities of current opioid drugs and without the development of tolerance or addiction.