The sulfur atom in the vitamin biotin has previously been suggested to be essential in biotin's mechanism of action. In a series of investigations on structure-function relationships with biotin analogs not containing the sulfur atom, the biotin analogs, azabiotin, bisnorazabiotin, carbobiotin and isoazabiotin enhanced guanylate cyclase, an enzyme that has recently been demonstrated to be activated by biotin. These analogs increased guanylate cyclase activity two-fold in liver, cerebellum, heart, kidney and colon at 1 microM concentrations. The ED50 for stimulation of guanulate cyclase activity occurred at 0.1 microM for each of the biotin analogs. These data indicate that the sulfur atom is not essential in biotin's activation of guanylate cyclase since these analogs do not contain the sulfur atom. Studies on the ring structure of biotin revealed that even compounds with a single 5-membered ring (2-imidazolidone) could augment guanylate cyclase activity. The guanylate cyclase co-factor manganese was not essential for the enhancement of guanylate cyclase by these agents but a maximal activation of this enzyme by these analogs could not be obtained without manganese present.
A series of anthraquinonyl glucosaminosides (10a-e) were synthesized by Koenigs-Knorr glycosidation of the corresponding aglycones (11a-e) with bromo sugar 12 followed by saponification. These glycosides were intended to serve as models to study the role played by the hydroxyl substituents on the aglycone portion of the antitumor anthracycline antibiotics. Superoxide generation as measured in rat heart sarcosomes was found to increase with the addition of successive hydroxyl groups to the anthraquinone nucleus. The 1,8-dihydroxy pattern was determined to generate significantly less superoxide than the 1,4-dihydroxy pattern. Hydroxyl substitution was also observed to stabilize the complex formed between the anthraquinones and DNA and was required for antibacterial activity against a number of Gram-positive organisms.
A totally synthetic route to the antibacterial fungal metabolite nectriapyrone (1) has been achieved by condensation of methylmalonyl dichloride with ethyl trans‐4‐methyl‐3‐oxo‐4‐hexenoate followed by hydrolysis, decarboxylation, and methylation of the resulting 3‐methyl‐4‐hydroxy‐5‐carbethoxy‐6‐(trans‐1‐methyl‐1‐propenyl)‐2‐pyrone. Exploration of an alternate scheme involving the dehydrogenation of 6‐substituted‐4‐methoxy‐5,6‐dihydro‐2‐pyrones, prepared by Reformatsky reaction of ethyl γ‐bromo‐β‐methoxycrotonate with various aldehydes, was abandoned since it did not appear to have general applicability to the preparation of nectriapyrone and its analogs.
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