Comparison of in vitro activities of camptothecin and nitidine derivatives against fungal and cancer cells.
The activities of a series of camptothecin and nitidine derivatives that might interact with topoisomerase I were compared against yeast and cancer cell lines. Our findings reveal that structural modifications to camptothecin derivatives have profound effects on the topoisomerase I-drug poison complex in cells. Although the water-soluble anticancer agents topotecan and irinotecan are less active than the original structure, camptothecin, other derivatives or analogs with substitutions that increase compound solubility have also increased antifungal activities. In fact, a water-soluble prodrug appears to penetrate into the cell and release its active form; the resulting effect in complex with Cryptococcus neoformans topoisomerase I is a fungicidal response and also potent antitumor activity. Some of the compounds that are not toxic to wild-type yeast cells are extremely toxic to the yeast cells when the C. neoformans topoisomerase I target is overexpressed. With the known antifungal mechanism of a camptothecin-topoisomerase I complex as a cellular poison, these findings indicate that drug entry may be extremely important for antifungal activity. Nitidine chloride exhibits antifungal activity against yeast cells through a mechanism(s) other than topoisomerase I and appears to be less active than camptothecin analogs against tumor cells. Finally, some camptothecin analogs exhibit synergistic antifungal activity against yeast cells in combination with amphotericin B in vitro. Our results suggest that camptothecin and/or nitidine derivatives can exhibit potent antifungal activity and that the activities of camptothecin derivatives with existing antifungal drugs may be synergistic against pathogenic fungi. These new compounds, which exhibit potent antitumor activities, will likely require further structural changes to find more selective activity against fungal versus mammalian cells to hold promise as a new class of antifungal agents.
Del Poeta
M
M
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Chen
S F
SF
Von Hoff
D
D
Dykstra
C C
CC
Wani
M C
MC
Manikumar
G
G
Heitman
J
J
Wall
M E
ME
Perfect
J R
JR
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D053119:Benzophenanthridines; D002166:Camptothecin / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D003470:Culture Media; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy; D008826:Microbial Sensitivity Tests; D010617:Phenanthridines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D059004:Topoisomerase I Inhibitors; D014170:Transformation, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D003470:Culture Media; D004791:Enzyme Inhibitors; D010617:Phenanthridines; D059004:Topoisomerase I Inhibitors; C013615:nitidine; D002166:Camptothecin