| Cancer continues to be a leading cause of death in the United States. Natural products obtained from plants have been the source of many approved anticancer drugs. This dissertation study is part of a multi-institutional collaborative program project entitled "Discovery of Anticancer Agents of Diverse Natural Origin". The overall aim of this project is the discovery of new natural product anticancer lead compounds from aquatic cyanobacteria, filamentous fungi, and tropical plants. The work presented herein focuses on the discovery of new anticancer lead agents from tropical plants. Two tropical plants of the family Fabaceae (Indigofera spicata and Millettia caerulea), collected in Vietnam, were investigated as possible sources of anticancer lead compounds.;Cytotoxicity-guided isolation of the chloroform extract of the combined flowers, fruits, leaves, and twigs of I. spicata resulted in the purification of four new flavanones (67, 71, 74, and 76) and six known compounds inclusive of three rotenoids (68, 70, and 73), two flavanones (69 and 72), and a chalcone (75), in addition to a semi-synthetic chalcone (77). Three cytotoxic compounds (68, 70, and 73) were identified with 50% inhibitory concentration (IC 50) values of less than 10 muM. cis-(6abeta,12abeta)- Hydroxyrotenone (68) and rotenone (70) showed submicromolar activities against HT-29 and 697 cells. Compounds 68 and 70 were non-toxic to normal colon cells. Compound 68 was investigated in an in vivo hollow fiber assay. Nine (68, 70-77) out of ten compounds evaluated in a quinone reductase induction assay were active, each with a concentration required to double (CD) quinone reductase activity value of less than 10 muM. The new compound, (+)-5-methoxypurpurin (74), was identified as a possible lead agent for cancer chemoprevention, with a CD value of 0.2 muM and no cytoxicity to the host cells.;Cytotoxicity-guided isolation of the chloroform extract of the fruits of M. caerulea resulted in the purification of one novel (143), two new (144-145), and eleven known rotenoids (68, 70, 73, 131-132, 135, 140-141, 146-148). The novel rotenoid, caeruleanone A (143), was found to contain an unprecedented arrangement of the D-ring and its structure was confirmed by single-crystal X-ray crystallographic analysis. As with I. spicata, cis-(6abeta,12abeta)-hydroxyrotenone (68) and rotenone (70) were isolated as the major cytotoxic components of the chloroform extract. The new compound, caeruleanone C (145), exhibited potent mitochondrial transmembrane potential (MTP) inhibition with an IC50 value of 0.07 muM, whereas deguelin (131) was active with an IC50 value of 3.3 muM. Also, tephrosin (73), showed nuclear factor kappa B (p65) inhibition with an IC50 value of 4.9 muM. Furthermore, seven (68, 70, 73, 141, 144- 145, and 148) out of thirteen compounds evaluated for quinone reductase induction activity displayed CD values of less than 10 muM. The new compounds, caeruleanone B (144) and C (145), showed potent activity with CD values of 0.9 and 1.0 muM, respectively, and exhibited no apparent cytoxicity to the host cells.;In sum, investigation of I. spicata and M. caerulea collected in Vietnam, provided novel, new and active lead compounds for possible development to combat cancer. |
