Tylosin derivatives

Other macrohdes have been prepared which represent hybrids of stmctures within the 14-membered family, within the 16-membered family, or between the two families. These hybrids have been made by chemical, bioconversion, or genetic manipulations. The 9-0-[(2-methoxyethoxy)methyl]oxime of tylosin (Table 7) was synthesized, using the oxime found in roxithromycin (33) (369). 3-0-Cladinosyl derivatives of 16-membered macrohdes were synthesized in which the neutral sugar of erythromycin (Table 3) was attached to tylosin derivatives at thek 3-hydroxyl group, analogous to its position in erythromycin... 

Figure 8.5 Tylosin derivatives obtained by expressing sugar genes...

Figu re 8.6 Tylosin derivatives obtained by combining gene inactivation, gene expression and feeding experiments. 

R Okamoto, H Nomura, M Tsuchiya, H Tsunekawa, T Fukumoto, T Inui, T Sawa, T Takeuchi, H Umezawa. The activity of 4"-<9-acylated tylosin derivatives against macrolide-resistant Gram-positive bacteria. J Antibiot 32 542-544, 1979. 

M Tsuchiya, M Hamada, T Takeuchi, H Umezawa, K Yamamoto, H Tanaka, K Kiyoshima, S Mori, R Okamato. Studies of tylosin derivatives effective against macrolide-resistant strains synthesis and structure-activity relations. J Antibiot 35 661-672, 1982. 

Michael addition of thiols across the 10,11-double bond has occurred in tylosin derivatives in which the aldehyde had been protected as its dithioketal [134, 139] a comment about successful Michael additions of amines was also... 

Hydrolysis of both neutral sugars from tylosin yields S-O-mycaminosyltylonolide (OMT) (51, R = CHO, R = R" = OH) (238). However, this compound is more conveniendy obtained by hydrolysis of mycarose from the fermentation-derived demycinosyltylosin. Analogous hydrolyses of mycarose from DMOT, GS-77-3, and GS-77-1 yield, respectively, 23-deoxy-5-0-mycaminosyltylonohde (DOMT), 20-deoxo-5-O-mycaminosyltylonohde (GS-77-4), and 5-0-mycaminosyltylactone (GS-77-2), all given in Table 9 (246,250,280). 

The enhanced activity from acylation of the 3- and 4 -hydroxyl groups of leucomycin prompted analogous studies of tylosin. Bioconversion of tylosin by S. thermotokrans yielded 3- and/or 4 -0-acyl derivatives possessing increased activity against certain resistant microorganisms and higher... 

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

By definition, the fraction that enters the circulatory system is eliminated by extrarenal mechanisms (usually metabolism by the liver and other tissues) and is derived by the difference from renal excretion that is, 1 — Fg. The excretory organs are able to eliminate polar compounds such as tetracycline and tylosin more efficiently than compounds that are highly soluble in lipids (i.e., lipophilic) such as metronidazole, erythromycin, clindamycin, and trimethoporin. Thus, the highly lipophilic compounds will not be eliminated until they are metabolized to more polar intermediates. 

Erythromycin A 64 and spinosyns A and D 65a/65b are important macrolides produced by Saccharopolyspora erythraea and Sacch. spinosa, respectively. Compound 65a contains per-O-methylated L-rhamnose and D-forosamine attached O-glycosidically to the aglycone. Gene knockouts in respective strains as well as expression of various sugar cassettes (along with appropriate GT gene(s)) in Sacch. erythraea mutants led to production of many derivatives of 64 and 65a and tylosin [111-114],... 

R Okamoto, T Fukumoto, H Nomura, K Kiyoshima, K Nakamura, A Takamatsu, H Naganawa, T Takeuchi, H Umezawa. Physico-chemical properties of new acyl derivatives of tylosin produced by microbial transformation. J Antibiot 33 1300-1308, 1980. 

HA Kirst, M Debono, KE Willard, BA Truedell, JE Toth, JR Turner, DR Berry, BB Briggs, DS Fukuda, VM Daupert, AM Felty-Duckworth, JL Ott, FT Counter. Preparation and evaluation of 3,4"-ester derivatives of 16-membered macrolide antibiotics related to tylosin. J Antibiot 39 1724-1735, 1986. 

Reduction of an aminal (derived from tylosine ) with sodium cyanoborohydride has also been used to prepare the corresponding tertiary RSMA.222... 

Biological activity of the macrolide derived from tylosin against Pasteurella multocida and P. haemolytica (in particular) in vitro and P. multicida (in particular) in vivo has been tested on chicks. Remarkable inhibition of these viruses is obtained. It is also found active against Staphylococcus aureus, Streptococcus pyogenes and pneumoniae, Haemophilus influenzae, Mycoplasma gallisepticum, synoviae, hyorhinis and hyopneumoniae 222... 

Omura, S., Miyano, K., Matsubaha, H., Nakagawa, a.. Novel dimeric derivatives of leucomycins and tylosin, sixteen-mem-bered macrolides. J. Med. Chem. 1982,... 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

The functional group tolerance possible with NaBHsCN is even mote amply illustrated by the successful reductive amination of the C-20 aldehyde in tylosin (21) with several amines,of the (T-3a aldehyde of the chlorophyll derivative Chi b (22) with NH3 (80% yield),and the C-11 aldehyde of the modified tetrodotoxin derivative (23) with several amino acids. ... 

The improved in vitro spectrum, in vivo efficacy, and pharmacokinetics of certain esters of leucomycin-related macrolides logically led to the synthesis of analogous esters of tylosin. 3- and 4"-0-acyl derivatives were initially prepared by bioconversions with Streptomyces thermotolerans, a producer of carbomycin [76], From this small group, 3-0-acetyl-4"-0-isovalerylty-losin (AlV-tylosin) (14) Figure 5.6) was chosen for further study because of its activity against some tylosin-resistant organisms and its improved oral therapeutic and pharmacokinetic effects [61, 77], AlV-tylosin has now been commercially developed as a new veterinary antibiotic. 

Chemical acylation of tylosin subsequently yielded a larger series of esters from which 4"-0-(4-methoxyphenylacetyl)tylosin (15) Figure 5.6) has emerged to the stage of preclinical studies due to its activity against certain resistant organisms and its improved metabolic stability [78-80], Several tylosin-related factors have also been acylated by chemical and biochemical methods [81-84], In addition to esters, 4"-0-alkyl and 4"-deoxy derivatives of tylosin have been prepared, but none was superior to compound (15) [85],... 

Other reductive aminations of tylosin-related macrolides have been reported, including the synthesis of dimeric moieties which retain antibacterial activity [92,93]. Other modifications of the aldehyde group include a variety of hydrazone derivatives, reduction products, and C-alkylated analogues [83, 94]. 

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