Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations

Twenty-two compounds belonging to several classes of polyamine analogs have been examined for their ability to inhibit the growth of the human malaria parasite Plasmodium falciparum in vitro and in vivo. Four lead compounds from the thiourea sub-series and one compound from the urea-based analogs were found to be potent inhibitors of both chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) strains of Plasmodium with IC₅₀ values ranging from 150 to 460 nM. In addition, the compound RHW, N1,N7-bis (3-(cyclohexylmethylamino) propyl) heptane-1,7-diamine tetrabromide was found to inhibit Dd2 with an IC₅₀ of 200 nM. When RHW was administered to P. yoelii-infected mice at 35 mg/kg for 4 days, it significantly reduced parasitemia. RHW was also assayed in combination with the ornithine decarboxylase inhibitor difluoromethylornithine, and the two drugs were found not to have synergistic antimalarial activity. Furthermore, these inhibitors led to decreased cellular spermidine and spermine levels in P. falciparum, suggesting that they exert their antimalarial activities by inhibition of spermidine synthase

Regioselective binding of spermine, N1,N12-bismethylspermine, and N1,N12-bisethylspermine to tRNAPhe as revealed by 750 MHz 1H-NMR and its possible correlation with cell cycling and cytotoxicity

The binding of spermine (SPM), N¹,N12-bismethylspermine (BMS) and N¹,N12-bisethylspermine (BES) to tRNA Phe was studied using ¹H-NMR at 750 MHz. The polyamines were enriched in 13C at the 5-CH2 and 8-CH2 residues and the nuclear Overhauser enhancement (NOE) cross peaks connecting the ¹H-NMR resonances of the13C-methylenes and several base paired imino protons of tRNA Phe were obtained using 1D13C-half filteredspectra. It was found that while SPM and BMS bind to the N(3)-H of base pairs T54-m¹A58, U50-A64 and U52-A62, BES binds only to T54-m¹A58 and U50-A64. This regioselectivity in the binding of the three polyamines to tRNA was correlated with their biological effects on cell growth. Using human melanoma cancer cells (MALME-3M), we found that SPM and BMS were without effect and cytostatic, respectively, while BES was distinctly cytotoxic. The latter also affected cell cycling and, at variance with SPM and BMS, lead to a distinctG1/S cell cycle arrest