Macrolide antibiotics cytotoxicity

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Rapamycin (sirolimus 2), isolated from Streptomyces hygroscopicus, is a highly functionalized 31-membered macrolide that exhibits potent antibiotic, cytotoxic, and immunosuppressive activity. FK506 (1) and rapamycin (2) are the structurally related macrolides (Fig. 1) thus, rapamycin possesses an a,p-diketoamide hemi-ketal system, a pipecolic acid moiety, 1,2,4-trisubstituted cyclohexane, and trisub-stituted tetrahydropyran rings, which are similar to those of FK506. In addition to these units, rapamycin (2) includes an ( , , )-triene moiety, two stereochemically complex aldol units, and 15 chiral centers beyond those found in FK506. 

Brefeldin (96), an octaketide macrolide with antiviral, cytotoxic, can-cerostatic and phytotoxic activity, was active (50 jig/ml) towards Anguil-lula aceti [142, 157]. Radicicol (monorden) (97), a macrolide antibiotic produced by Deuteromycetes, possesses cytotoxic, antiprotozoal and anti-neoplastic activity [158]. The diethyl ether derivative showed weak activity (LD50 0.2 mg/ml) against a soil nematode, but the cytotoxicity was considerably higher (LD50 3.1 ig/ml) [159]. 

MaytansinoMs (maitansinoids). A group of macrolide antibiotics with antileukemic, antimitotic, and cytotoxic properties from the Ethiopian shrub Maytenus ovatus, other Celastraceae, and Trewia nudiflora (Eu-phorbiaceae) as well as the Japanese mosses Isothe-cium subdiversiforme and Thamnobryum sandei (Neckeraceae). 

Macrolide antibiotic. Constit. of Amphidinium sp. Cytotoxic agent. Amorph. solid. [a]j/ —50 (c, 0.1 in CeHe). 

C32H52O, M 532.759 Macrolide antibiotic. Prod, by Streptomyces graminofaciens. Cytotoxic agent. Powder. Mp 55-62°. [a] 4-48 (c, 0.05 in MeOH). 

Macrolide antibiotic. Isol. from the marine sponge Forcepia sp. Cytotoxic agent. Pale orange solid, [a] -f 24.4 (c, 0.04 in CDCI3). 

Femandez-Chimeno, I. R., Canedo, L., Espliego, R, Gravalos, D., De La Calle, F, Femandez-Puentes, J. L., and Romeo, F. (2000). IB-96212, a novel cytotoxic macrolide produced by a marine Micromonospora. I. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. 53,474-478. 

Jansen, R., Irschik, H., Reichenbach, H., and Hofle, G. (1997) Antibiotics from gliding bacteria, LXXX. Chivosazoles A-F novel antifungal and cytotoxic macrolides from Sorangium cdlidosum (Myxobacteria). Liebigs Ann. Chem.,... 

Several spedes of dinofiagellates, members of the genera Amphidinium, Goniodoma (Gonyaulax) and Prorocentrum, produce (in addition to the toxins described previously) fungicidal and cytotoxic macrolides whose structures are similar to those of the antibiotics produced by Streptomy-ces. Most of these substances, which are very numerous. 

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