Title

A Solution Conformation Analysis of Forocidins I and Isoforocidins I Using NMR and Molecular Modeling

Document Type

Article

Publication Date

4-1995

Publication Source

Pharmaceutical Research

Abstract

Spiramycins, discovered in 1954, are 16-membered macrolides produced by Streptomyces ambofaciens (1). They show antimicrobial activity against Toxoplasma gondii and Cryptosporidium, protozoal opportunistic infections associated with AIDS (2,3). The correlation between chemical structure and biological activity of the family of 16- membered macrolides is limited but studies indicate that there is a loss of activity in spiramycins devoid of sugar moieties. The absolute stereochemical requirements and their effect on the activity of this series of compounds has yet to be investigated.

We have recently presented a complete NMR spectral characterization ofthe spiramycins I and III (4). Our current interests involve producing derivatives of the spiramycins employing techniques such as selective microbial biotransformations of spiramycin biosynthetic precursors such as the forocidins (acid hydrolytic products of spiramycin I) (Fig. 1). This endeavor has required a complete and explicit spectral characterization of both the spiramycins (4) as well as the forocidins.

The major objective of the present study was to determine the conformation of the forocidins in solution using molecular dynamics and two-dimensional NMR data. The dihedral angles and coupling constants have been estimated using extended Karplus-type equations, the results of which have been compared to those obtained from the X-ray data for 13-0H demycarosyl Leucomycin A3 (4,5). With an understanding of the solution conformation of this spiramycin hydrolytic product, one may better deduce how the parent compound, spiramycin, as well as analogs of spiramycin affect biological activity. lH-NMR and 13C-NMR assignments (Tables 1 and 2) of the forocidins I (6,7) (Figure 3) and the isoforocidins I (4,5) (Figure 4) are also reported here.

Inclusive pages

621–629

ISBN/ISSN

0724-8741

Comments

Permission documentation is on file.

Publisher

Springer

Volume

12

Issue

4

Peer Reviewed

yes