Mechanism of forming trimer, self-assembling nano-particle and inhibiting tumor growth of small molecule CIPPCT

The mechanisms of small molecules forming nanospecies and the effect of the nanospecies of small molecules on their pharmacological actions remain to be elucidated. As one of our efforts here, a uPA inhibitor, (5aS,12S,14aS)-5,14-dioxo-12-(2-tryptophanylthreo-nylbenzylester- N -yl-ethyl-1-yl)-1,2,3,5,5a,6,11,12,14,14a-decahydro-5 H ,14 H -pyrolo[1,2:4,5]-pyrazino[1,2:1,6]pyrido[3,4- b ]indole (CIPPCT) was presented. Energy-minimization, FT-MS and 2-D ROESY spectra defined CIPPCT taking -like conformation, and the intermolecular association drove CIPPCT to form a finger ring-like trimer. Images from transmission electron, scanning electron and atomic force microscopies consistently visualized that in aqueous solution at pH 6.7 and 10 −10 M concentration, CIPPCT generally assembled nanoparticles of 9–67 nm in diameter. Mesoscale simulation demonstrated that a nanoparticle 9.4 nm in diameter contained 350 trimers. In vivo CIPPCT dose-dependently inhibited tumor growth in S180 mice. An ELISA assay confirmed that CIPPCT concentration-dependently downregulated serum uPA. The nanoparticles of CIPPCT are capable of occurring in mouse plasma and adhering on HeLa cells, and nanosized CIPPCT directly correlates the downregulation of uPA with inhibition of tumor growth.