Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A.
BACKGROUND
Dynemicin A is an exceedingly potent antitumor antibiotic derived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH or glutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modify the structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product.


RESULTS
A multistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed. The absolute configuration of natural dynemicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation. The route that was developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to non-natural dynemicins of wide structural variability by modifications of these fragments. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH.


CONCLUSIONS
Enantiomerically pure dynemicin A is now available by laboratory synthesis. The natural, (+)-enantiomer of dynemicin A is shown to possess the 2S, 3S, 4S, 7R, 8R configuration. A wide variety of heretofore unavailable, active analogs of dynemicin A have been prepared and are found to produce subtle variations in sequence specificity of DNA cleavage compared to the natural product and, of potentially greater significance, display variations in the efficiency of DNA cleavage as a function of the activating agent.
Myers
A G
AG
Arnold Laboratory of Chemical Synthesis, California Institute of Technology, Pasadena 91125, USA.
Fraley
M E
ME
Tom
N J
NJ
Cohen
S B
SB
Madar
D J
DJ
D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D053281:Enediynes; D005285:Fermentation; D008847:Micromonospora / Q000378:metabolism; D010084:Oxidation-Reduction; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D013237:Stereoisomerism
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D004247:DNA; C061229:dynemicin A