Browsing by Author "Molinero, Anthony A."
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- The biosynthesis of virginiamycin S₁Molinero, Anthony A. (Virginia Polytechnic Institute and State University, 1982)The biosynthesis of virginiamycin S₁, a macrocyclic peptidolactone antibiotic, was studied by growing a strain of Streptomyces virginiae in a complex medium and observing the incorporation of radiolabeled compounds into the antibiotic. These studies have established several of the biosynthetic precursors of virginiamycin S₁. L-(U-14C)-Proline and L-(U-14C)-threonine were effectively incorporated into the respective amino acid components in the antibiotic. N-Methyl-L-phenylalanine was shown to arise from L-(U-14C)-phenylalanine and L-(methyl-14C)-methionine. L-(U-14C)-Phenylalanine was also efficiently incorporated into L-phenylglycine. The origin of the remaining three components was less clear. A small amount of L-(U-14C)-threonine was observed in D-α-aminobutyric acid. A biosynthetic pathway is known between these two amino acids which suggests that L-threonine may be the biosynthetic precursor of D-α-aminobutyric acid. Both L-(U-14C)-aspartic acid and L-(U-14C)-lysine were incorporated into 4-oxo-L-pipecolic acid and 3-hydroxypicolinic acid. A biosynthetic pathway was hypothesized to explain these results.
- The chemistry of cephalomannineMolinero, Anthony A. (Virginia Tech, 1995)Cephalomannine is a naturally occurring taxane diterpenoid closely related to the potent anticancer agent Taxol. Three aspects of its chemistry were examined. First, cephalomannine was converted to Taxol. This conversion was accomplished by the reaction of a 2'- benzoyl-7-Troc cephalomannine/Taxol mixture with oxalyl chloride to generate a common oxamic acid intermediate. Treatment of this intermediate with diphenylcarbodiimide cleaved the N-oxalyl group which resulted in a spontaneous transfer of the 2'-benzoyl group to the 3'-N position. Deprotection of the 7-Troc group afforded Taxol. Second, a number of 3'-N-acyl cephalomannine and Taxol analogs were prepared and their biological activity determined. The N-tigloyl group of cephalomannine was modified by oxygenation and halogenation to yield several cephalomannine derivatives. The Taxol analogs were prepared by coupling a protected side chain to baccatin III, deprotecting, and acylating the resulting free amine. This methodology was used to prepare several oxalyl and halogenated analogs as well as N-(phenylglyoxyl) and N-crotonyl derivatives. One derivative in particular, N-debenzoyl-N-(2"-bromopropenoyl)taxol, was found to be significantly more active than Taxol. Third, Taxotere, 10- acetyltaxotere, N-debenzoyl-N-(phenoxyacetyl)taxol, and the cephalomannine diol were synthetically prepared for testing in several tubulin polymerization systems. Earlier studies had shown that some Taxol analogs had the ability to stabilize tubulin polymers to cold, but failed to induce assembly as does Taxol. The compounds prepared were used to investigate the differences and this led to the conclusion that the hypernucleation of tubulin assembly and polymer stabilization observed with Taxol represent two distinct properties of the drug.
- Method for the conversion of cephalomannine to taxol and for the preparation of n-acyl analogs of taxol(United States Patent and Trademark Office, 1995-11-28)The natural product cephalomannine can be converted to the important anticancer natural product taxol by a simple process involving the steps of dihydroxylation to give cephalomannine-diols, diol cleavage, benzoylation at the 2'-position and reaction with a 1,2-diamine. The same process when applied to mixtures of taxol and cephalomannine makes it possible to separate taxol from cephalomannine-diols by simple flash-chromatography after the dihydroxylation step. If the benzoylation step is avoided in the above sequence of conversions, the process leads to the free amine (N-debenzoyltaxol). In addition, the selection of an acylating reagent other than that with the benzoyl group for acylation of the free amine (N-debenzoyltaxol), allows the preparation of taxol analogs with other N-acyl substituents.