Lincomycin. XI. Synthesis and structure of clindamycin, a potent antibacterial agent

Abstract

lions, except that the sublimtatiou of the crude product, required a longer time (2 days, 60°oil bath) and the sublimate was recrystallized from EtzO-low boiling petr ether; 25% yield; nip 87.5 ,S9°. Anal. (C,0H,NBrF) C, , N.General Procedure for Preparation of Urea and Thiourea Derivatives of 3-Aminoisoquinolines 22, 23,24.--The urea derivatives were prepared by condensation of the 3-aminuisoquinolilies with the corresponding isocyanates and isothiocyanates in warm CeH6 solutions (several days). The yields (purified) were 85% for 22, 01 % for 23, and 30% for 24. liecrystallization solvents and elements analyzed are given in Table I.General Procedure for Preparation of Sulfonamides of 3-Ammoisoquinolir.es. -The sulfonamides 18, 20, and 21 were obtained by heating at ca. 00°the aminoisoquinolines with the corresponding sulfonyl chlorides in pyridine, 'fire yields of purified materials were 5(1% for 18, 90% for 20, and 55% for 21 I!, 1). and F. Karan 'filie acetamide 20 was deacetylated in a refluxing (30 mini mi.xi lire of EtOH-concd HCI (5: 1) for 30 min and the sulfa nil,amide 19 was isolated in ca. 60% yield as the free liase."-( 3-Isoquinolyl )crotonamide ( 15).• -In aunt tempt to aminate ,Y-i3-isoqmnolyl)-3-ehlorobutyramide1 with excess of ,Y,.\dimethyl-.Y'-ethylethylenediamine in refluxing CHCfii only the elimination product .Y-(3-isoquiiiolyI icrotonamide was isolated (48%), mp 150-132°(Table I).-Y-(3-Isoquinolyl)acrylamide ( 14). This compound was isolated as tlie elimination product of .V-(3-isoquiiu:>lyl)-3-ohloro-propionamide1 with PhNHMe in refluxing CHCl, in tlie presence of Na-XO:, (Table U. 3-Benzamidoisoquinolines. -A'-(3-lsoquinolyljbenzamiile i l(i) and .\'-('3-isoquinoiyl)-3-nitmbenzamide (17) were obtained in fair yields by the reactions of 3-aminoqiiiiioliiie with the nppmpriale benzoyl rliiiirides in refluxing ('«Hr, íTable 11.

Pretrichodermamide C and N-methylpretrichodermamide B, two new cytotoxic epidithiodiketopiperazines from hyper saline lake derived Penicillium sp.

“…Naturally occurring chlorinated compounds have assumed an important role in the field of natural products. The presence of a chlorine atom is crucial for the biological activity of a plethora of natural products such as the antibiotics clindamycin (Birkenmeyer and Kagan, 1970), vancomycin (Harris et al, 1985), chloramphenicol, and griseofulvin (Crosse et al, 1964), as well as the antitumor compounds cryptophycin (Golakoti et al, 1995), rebeccamycin (Bush et al, 1987), and clavulone (Nagaoka et al, 1985). Pretrichodermamide C (2) provides a further example for the importance of halogene substituents with regard to the biological activity of natural products.…”

Physiology, Biochemistry, and Applications of F420- and Fo-Dependent Redox Reactions

“…Encoded by the oxytetracycline (oxy), chlorotetracycline (ctc), and dactylocyclinone (dac) gene clusters (29), these enzymes are members of the flavin/deazaflavin oxidoreductase (FDOR) superfamily (30) and utilize F 420 H 2 reduced through the action of Fno (387). F 420 is also required for the synthesis of lincosamide antibiotics by Streptomyces lincolnensis strains (146,388,389), including lincomycin, the precursor of the clinical semisynthetic antibiotic clindamycin (390). On the basis of the accumulation of 4-propylidene-3,4-dihydropyrrole-2-carboxylic acid by strains unable to biosynthesize F 420 , it is proposed that an F 420 H 2 -dependent reductase catalyzes the reduction of the imine moiety of the dihydropyrrole to tetrapyrrole (Fig.…”

Influence of chlorine substituents on biological activity of chemicals

“…This principle was discovered long ago by Nature with its own chlorinated biologically active ingredients (Scheme 2). The chlorine substituent is essential for significant biological activity in a number of natural products such as the antibiotics clindamycin 1 [9], vancomycin 2 [10], chloramphenicol 3, and griseofulvin 4 [11], and the antitumour compounds cryptophycin 5 [12], rebeccamycin 6 [13], clavulon 7 [14], neopyrollomycin 8 [15] and astin A 9 [16]. In case of the natural azaphilons 10 [17] the chlorine exerts its enhancing effect with regard to binding to the endothellin receptor of rats and rabbits in quantitatively quite a different way.…”