Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L.

The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.

Ring expansions of acyloxy nitroso compounds.

Treatment of cyclopentanone and cyclobutanone-derived oximes with lead (IV) tetraacetate gives the bright blue acyloxy nitroso compounds, which upon basic hydrolysis yields the ring expansion product cyclic hydroxamic acids in 12-81% yield. Reactions of substituted cyclopentanones provide ring expanded products where the -NOH group regioselectively inserts to the more substituted position and gives a better yield compared to the treatment of the same ketone with a basic solution of Piloty's acid. Reaction of phosphines with acyloxy nitroso compounds generally generates a ring-expanded Beckmann rearrangement product that can be hydrolyzed to the corresponding lactam. Acyloxy nitroso compounds that undergo rapid hydrolysis to HNO do not show this ring expansion reactivity. These results further demonstrate the versatility of acyloxy nitroso compound to yield structurally complex materials.

Selective manipulation of the inositol metabolic pathway for induction of salt-tolerance in indica rice variety.

Halophytes are rich sources of salt stress tolerance genes which have often been utilized for introduction of salt-tolerance character in salt-sensitive plants. In the present study, we overexpressed PcINO1 and PcIMT1 gene(s), earlier characterized in this laboratory from wild halophytic rice Porteresia coarctata, into IR64 indica rice either singly or in combination and assessed their role in conferring salt-tolerance. Homozygous T3/T4 transgenic plants revealed that PcINO1 transformed transgenic rice lines exhibit significantly higher tolerance upto 200 mM or higher salt concentration with negligible compromise in their growth or other physiological parameters compared to the untransformed system grown without stress. The PcIMT1-lines or the double transgenic lines (DC1) having PcINO1 and PcIMT1 introgressed together, were less efficient in such respect. Comparison of inositol and/or pinitol pool in three types of transgenic plants suggests that plants whose inositol production remains uninterrupted under stress by the functional PcINO1 protein, showed normal growth as in the wild-type plants without stress. It is conceivable that inositol itself acts as a stress-ameliorator and/or as a switch for a number of other pathways important for imparting salt-tolerance. Such selective manipulation of the inositol metabolic pathway may be one of the ways to combat salt stress in plants.