The synthesis and evaluation of 10- and 12-membered ring benzofused enediyne amino acids.
The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA. N-Arylsulfonyl substitution on the ring promoted the cyclization, when compared to N-mesyl or acyl substitution, possibly because of a pi-pi stacking effect as an endo-relationship of the aryl group with the enediyne was demonstrated in both the solid state and in solution. The 12-membered ring enediyne dipeptide (11) was inert to the Bergman cyclization under a variety of conditions. When this substrate was irradiated with ultraviolet light, regio- and stereospecific reduction was observed in which one of the alkynes was reduced to a Z-olefin (47).
Du
Yanming
Y
Drug Discovery Division, Johnson, & Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA.
Creighton
Christopher J
CJ
Yan
Zhengyin
Z
Gauthier
Diane A
DA
Dahl
John P
JP
Zhao
Boyu
B
Belkowski
Stanley M
SM
Reitz
Allen B
AB
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000598:Amino Acids, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001554:Benzene / Q000737:chemistry*; D002417:Cattle; D018360:Crystallography, X-Ray; D003500:Cyclization; D004249:DNA Damage / Q000187:drug effects; D053281:Enediynes; D015394:Molecular Structure; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000187:drug effects
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D053281:Enediynes; D012710:Serum Albumin, Bovine; D001554:Benzene