Semisynthetic derivatives

Antituberculin Agents. Rifampin [13292-46-17, a semisynthetic derivative of rifamycin SV, is a most valuable dmg for treatment of tuberculosis, an infection caused by mycobacteria, leprosy, and an expanding range of other infections (23). Cycloserine [64-41-7] has been used to a limited extent for treatment of tuberculosis as a reserve dmg. Although cycloserine inhibits bacteria by interfering with their cell wall biosynthesis, it has toxic side effects in humans in the form of neurotoxicity. Capreomycin [11003-38-6] and to a much lesser extent viomycin [32988-50-4] both of which are peptides, have also been used for treatment of this disease. 

Many labeling systems have been used for dalbaheptide stmctures. The one used herein, where each of the seven amino acids is identified by a number (see Table 2) and each atom by a letter, is widely appHed because it permits easy comparison of and nmr data (31). The lUPAC system, utilised in Chemicaly hstracts and generally in the description of semisynthetic derivatives, requires decodification for comparison of different dalbaheptides (83). 

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macroHdes some of the derivatives ate being commercially launched (116). 

Semisynthetic Derivatives. No significant improvements in activity have resulted from modifications of the 3-, 9-, 2and/01 4"-hydioxyl groups (314). 3 -0-Acyl derivatives have not been found via fermentation, but chemical acylation of the 3 -hydroxyl group yields products having good antibiotic activity and better pharmacokinetics than the patent macroHdes. Two such compounds have been developed (315,316) ... 

Fig. 2. Semisynthetic derivatives of I6-membered macroHdes rokitamycin (62, R = R " = H, R = butyryl, R" = propionyl) miokamycin (62,...

Rifampicin is the semisynthetic derivative used widely in the UK. Resistance to rifampicin is primarily due to chromosomal mutations resulting in an altered RNA polymerase which is less well inhibited by the drug. The mutations tend to be clustered within short conserved regions of the J3 subunit gene of RNA polymerase. Similar mutations have been found in all bacterial species studied thus far. 

Suloff, E. C Comparative study of semisynthetic derivative of natamycin and the parent antibiotic on the spoilage of shredded cheddar cheese. Thesis, Virginia Polytechnic Institute and State University, Blacksburg, VA, 1999, http // scholar. lib. vt.edu/theses/available/etd-... 

Marchi E, Mascellani G, Montecchi L, Brufani M, Cellai L L/105, a new semisynthetic derivative of rifamycin SV, synthesis and structure-activity relationship. Chemioterapia 1983 2 38. 

Several semisynthetic derivatives of yohimbine alkaloids show interesting pharmacological activity. For example, 17-methylthiomethoxyyohimbane stereoisomers (612 and 613) are valuable central nervous system depressants (349) and several hydrazides of yohimbinecarboxylic acid (614 and 615-type compounds) are useful cardiac stimulants, respiratory analeptics, and antihypertensives (350-353). 

Anhydroartemisinin (132), a semisynthetic derivative with very high antima-larial activity, was converted to the rearranged compound 136 and to the 9f5-hydroxylated derivative 133 by S. lavendulae L-105, whereas a Rhizopogon species (ATCC 36060) formed hydroxylated metabolites 134 and 135 [2121. Pre-... 

Newer and more generally usefnl macrolide antibiotics include azithromycin (Zithromax) and clarithromycin (Biaxin). These too are wide-spectrum antibiotics and both are semisynthetic derivatives of erythromycin. Like the tetracyclines, the macrolide antibiotics act as protein synthesis inhibitors and also do so by binding specifically to the bacterial ribosome, thongh at a site distinct from that of the tetracyclines. 

Apomorphine hydrochloride (44 Apokyn Bertek, 2004), is a semisynthetic derivative of opium alkaloid morphine (43) isolated from poppy (Papaver somniferum), and it has long been known for its erectile activity at the effective dose of 2-6 mg physicians discovered the effect over 100 years ago, but found the drug, at a much higher dose (ca. 200 mg), to be more suitable for poison victims as an emetic because it also causes serious nausea and vomiting. Apomorphine exerts its erectile effect at the central nervous system the drug has been found to be a non-selective dopamine agonist which activates both Di-like and D2-like... 

Zotarohmus (53 EndeavorT stent ABT-578 Medtronic, 2005), a semisynthetic derivative of sirolimus (34), was designed for use in stents with phosphorylcholine as a carrier coronary stents reduce early complications... 

The vast majority of compounds having the bisindole nucleus characteristic of the vinca structure with antitumor activity in experimental tumor systems bear a carboxyl function and a free tertiary hydroxyl group at C-3 of the vindoline moiety. The group of semisynthetic derivatives distinguished by the presence of a C-3 spiro-fused oxazolidine-l,3-dione are important exceptions to this generalization. 

The compound ultimately chosen for development was a semisynthetic derivative of the B series in which the 22,23 double bond is reduced (18). The mixture consisting of at least 80%... 

Ergot alkaloids contain lysergic acid (formula in A shows an amide). They act on uterine and vascular muscle. Ergo-metrine particularly stimulates the uterus. It readily induces a tonic contraction of the myometrium (tetanus uteri). This jeopardizes placental blood flow and fetal O2 supply. The semisynthetic derivative methylergometrine is therefore used only after delivery for uterine contractions that are too weak. 

Paclitaxel, from the bark of the pacific yew (Taxus brevifolia), inhibits disassembly of microtubules and induces atypical ones. Docetaxel is a semisynthetic derivative. 

Rifamycin SV (133, Fig. 23) is a naturally occurring macrocycle isolated from Nocardia mediterranei by Senti, Greco and Ballotta in 1959. It shows a high in vitro antibiotic activity through inhibition of DNA-dependent RNA polymerase, but bioavailability is low due to its poor water solubility. The semisynthetic derivative rifampicin (135) displays markedly higher water solubility and in vivo activity. We chose 3-formylrifamycin (134) as model macrocycle for the possibility of binding it to solid phase by hydrazone bond formation in a manner similar to rifampicin (Fig. 24). 

Artemisinin (18) is a natural product for which many semisynthetic derivatives have been generated. The major rationale to produce these derivatives was to deal with the low aqueous solubility of artemisinin and its short half-life in plasma. The lipid-soluble arteether (22) and artemether (23), and the water-soluble sodium artesunate (24), were designed for... 

As will be mentioned further in this chapter, the discovery of the anticancer drug, paclitaxel (21), was soon followed by sourcing issues due to the low yield of this compound in the source plant, Taxus brevifolia Nutt. This led to the semisynthesis of paclitaxel (21), from a precursor molecule, 10-deacetylbaccatin III, readily available from the leaves of Taxus baccata L., a renewable source with high yields of this compound.Docetaxel (37) is a second taxane class anticancer drug and is a semisynthetic derivative of paclitaxel (21). ... 

Rifampin (Fig. 8) is semisynthetic derivative of Rifamycin B that was isolated from Sterptomyces mediterranei. 5 F 52 niode of action was confirmed... 

The most widely used agonists in medical practice are the opium alkaloids morphine and codeine. However, semisynthetic derivatives (hydromorphone, oxymorphone, hydrycodon, oxycodone), whose use is even preferred in certain cases, and strong, purely synthetic compounds (methadone, meperidin, fentanyl, sufentanyl, and others) have found wide use. 

Bromocriptine Bromocriptine, 2-bromoergocriptine (10.1.13), is a semisynthetic derivative of a natural ergot alkaloid, ergocriptin (a derivative of lysergic acid), which is synthesized by bromination of ergocriptin using M-bromosuccinimide [18,19]. 

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