Macrolides structure determination

The polyene macrolide filipin was isolated in 1955 from the cell culture filtrates of Sterptomyces filipinensis, and was later shown to be a mixture of four components [36]. Although too toxic for therapeutic use, the filipin complex has found widespread use as a histochemical stain for cholesterol and has even been used to quantitate cholesterol in cell membranes [37]. The flat structure of filipin III, the major component of the filipin complex, was assigned from a series of degradation studies [38]. Rychnovsky completed the structure determination by elucidating the relative and absolute stereochemistry [39]. The total synthesis plan for filipin III relied heavily on the cyanohydrin acetonide methodology discussed above. 

Hochlowski JE, Swanson SJ, Ranfranz LM, Whittem DN, Buko AM, McAlpine JB. (1987) Tiacumicins, a novel complex of 18-membered macrolides II isolation and structure determination. J Antibiot 40 575-588. 

Pathirana, C., Tapiolas, D.M., Jensen, P.R., Dwight, R., and Fenical, W., Structure determination of maduralide a new 24-membered ring macrolide glycoside produced by a marine bacterium (Actino-... 

The eggs of the nudibranch Hexabranchus sanguineus collected off the coast of Hawaii have yielded the macrolides ulapualide A (62) and ulapaulide B (63) (25) both of which incorporate the unprecedented trisoxazole moiety. These compounds were obtained as colorless oils whose structure determination was... 

In another natural product structure determination reported during 2002 that relied on cryoprobe technology, Gustafson et al.244 reported the structure of a new antitumor macrolide lactam, poecillastrin A (108) from the sponge Poecillastra sp. The study was complicated by the need for extensive 1H-13C HMBC data to assemble the structure and a sample of 800 pg (0.55 pmol). 

ABSTRACT Marine invertebrates such as ascidians, sponges and others are a prolific source of bioactive secondary metabolites. We have isolated a variety of marine natural products from the Okinawan marine invertebrates by using the sea urchin egg assay. Our recent work, the isolation, structure determination and activities of chlorinated macrolides, sesterterpenic acids, a bromotyrosine derivative, acetogenin derived endoperoxides, diterpene alkaloids, sesquiterpene quinones and spiro-sesquiterpenes, is presented in this article. The syntheses of these metabolites are also described. 

Bergquist, K. E., Obianwu, H., and Wickberg, B. (1989). Isolation and structure determination of a novel phorbol derivative in an intramolecular diester macrolide. J. Chem. Soc. Chem. Commun. 183-184. 

Polyene Macrolides. - 2.2.1 Pentaenes. Full details have now been published of the structure determination of lienomycin (111), a pentaene from... 

Douthwaite, S. and Champney, W.S. (2001) Structures of ketolides and macrolides determine their mode of interaction with the ribosomal target site. The Journal of Antimicrobial Chemotherapy, 48 (Suppl 2), 1. 

The relative and absolute stereochemistry of antimitotic macrolide archazolid A and B, originally isolated in the early nineties, has been determined on the basis of extensive high-field NMR studies, molecular modelling and chemical derivatization <06OL4751>. The proposed structures have yet to be confirmed by total synthesis. 

Sowinski and coworkers40 reported a structure of vacidin A (63), an aromatic hep-taene macrolide antibiotic. The constitution of vacidin A, a representative of the aromatic heptaene macrolide antibiotics, was established on the basis of 13C and H- H double quantum filtered correlated spectroscopy, rotating frame nuclear Overhauser effect spectroscopy, 7-resolved 11 as well as H-13C correlation NMR spectra. The geometry of the polyene chromophore was determined as 22E, 24E, 26E, 28Z, 30Z, 32E, 34E. 

Hirota and coworkers41 reported a planar structure of new polyene macrolide antibiotic YS-822A (65), which they isolated. XH and 13C NMR spectra of 65 showed a number of broad and overlapping signals, but the 1H-1H and 13C- H COSY spectra implied the existence of a mycosamine moiety and several other partial structures. The connectivity of these partial structures was established by extensive 2D NMR experiments, including homonuclear Hartmann-Hahn and heteronuclear multiple-bond connectivity measurements, which led to the determination of the gross planar structure of 65. 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC50 values are approximately 100-fold lower. This neutral macrolide suppresses the mixed lymphocyte reaction T-cell proliferation generation of cytotoxic T-cells production of T-cell derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). Structurally, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspeigualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the determination of their utility as immunosuppressive agents. 

The 2.10, 1.93, and 2.65 A crystal structures for the epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P 450epoK are the first crystal structures of an epothilone-binding protein solved. The epothilones are positioned with the macrolide ring roughly perpendicular to the heme plane and I helix, and the thiazole moiety provides key interactions that very likely are critical in determining substrate specificity <2003JBC44886>. 

The structures of two new pyrrolidine alkaloids, pandamarilactonine-A and -B isolated from Pandanus amaryllifolius Roxb, have been deduced by Takayama and co-workers with the help of vicinal Jhc and /hh couplings. Girault and co-workers have determined conformations of free and ribosome-bound macrolide antibiotics using NMR and molecular modelling. The authors analysed Vhc and /hh couplings of the proline and sugar part of lincomydn and clindamycin and of the macrocycle as well as desosamine part of HMR 3647 (telithromycin). ... 

In the first example, 2D NOESY spectra were used to define the stereochemistry in the synthetic cycloadduct 8.14 [7], a potential biomimetic precursor to the naturally occurring marine-sponge alkaloid Keramaphidine B, 8.15. This problem is essentially the same as that addressed for 8.7 above using the NOE difference experiment, but in this case the additional unsaturated sidechains caused extensive overlap in the proton spectrum and precluded the use of selective presaturation. Sufficient characteristic NOEs present in a 600 ms NOESY spectrum gave conclusive proof of the endo stereochemistry, as shown. Only positive NOEs were observed, consistent with a molecule of mass 436 daltons in chloroform. NOESY spectra have also been successfully applied to the structure elucidation of molecules for considerably greater mass and complexity, as illustrated by the cytotoxic macrolide cinachyrolide A, 8.16 [35], also from a marine sponge. The structure of the molecule was determined through extensive 600 MHz 2D NMR experiments, of which NOESY played... 

Pikromycin. Pikromycin (19, R = OH, R = H), the first macrolide discovered (77,78), is produced by S.felleus. Pikromycin is identical to amaromycin and albomycetin (79—81) and may be identical to proactinomycin (82—84). The structure of pikromycin was determined from chemical degradation, mass spectrometry, nmr, and x-ray crystallography (85-90). Its aglycone, pikronolide (20, R = OH), was produced by S. vene uelae (36). A derivative, kromycin (22, R = OH), was formed from pikromycin under acidic conditions (87,88,91) and more drastic conditions produced an intramolecular spiroketal of pikronolide named kromin (89,91). 10,11-Dihydropikromycin (21, R = OH, R = H), was also produced by S. vene uelae (92). 

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