Macrocyclic lactam antibiotics

Direct application of purified 68 to seeds suppressed damping-off disease in soil naturally infested with Pythium spp. The macrocyclic lactam antibiotic, xanthobaccin A (68), which has a characteristic 5,5,6-tricyclic skeleton and tetramic acid chromophore [148], displayed mycelial growth inhibition of A. cochlioides, Py. ultimum, and Ph. vignae f. sp. adzukicola at a range of 0.1-10 pg/ml. 

Macrocyclic lactam antibiotics consist of the ansamycin antibiotics and a number of other compounds which are classified as non-ansamycin macrocyclic lactams (Scheme 1). 

Isothiazole substituents have been attached to /3-lactam antibiotics and to macrocyclic antibiotics such as erythromycin. The sulfa drug, Sulfasomizole (244) also has good antibacterial activity. Thiosemicarbazones of 5-formyl- and 5-acetylisothiazoles show high activity against the pox group of viruses (65AHC(4)107). 

Seto and coworkers47 reported a study on viridenomycin (77), a novel 24-membered macrocyclic polyene lactam antibiotic. A new antitumor antibiotic, designated AL081,... 

Although the majority of reports of macrocycles in analytical chromatography have involved ligand association with the stationary phase, their use as mobile phase constituents has also been investigated. Lamb and Drake [11] showed that addition of water-soluble crown ethers to the mobile phase altered the retention of alkali metal cations on an underivatized reversed phase column. Nakagawa et al. [63-66] also used crown ether-containing mobile phases in the separation of protonated amines, amino acids and peptides, and [1-lactam antibiotics. 

Baker and Castro [69 e] reported that DCC, DPP A, or DPEC did not induce the macrocyclic lactam closure in the synthesis of the antitumor antibiotic ( + )-macbecin I, but it was achieved by mesitylenesulfonyl chloride. 

As examples of the non-ansamycin macrocyclic lactams, stubomycin (hitachimycin) was first isolated as an antitumor antibiotic [4-8]. Ikarugamycin [9], capsimycin [10], rapamycin and demethoxy-rapamycin [11-13] are other examples. Through the investigation of the biosynthesis of stubomycin (hitachimycin), it was found that the benzene ring of the P-phenylalanine moiety was involved as a chromophore outside of the macrocyclic moiety [5,14]. 

Other natural products whose syntheses were reported during the period of this Report, and which are worthy of more than a cursory inspection, include the antibiotic A-23187 (calcimycin) (213), the ansa-macrocyclic lactam maytansinol (214), and the lignan steganone (215). ... 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Another example of macrocyclic RCM with a diene-ene was disclosed in 2000 by Meyers and coworkers in the first total synthesis of griseoviridin (223) [ 107]. Griseoviridin is a highly complex member of the family of streptogramin antibiotics, featuring a 23-membered unsaturated bis-lactam core incorporat-... 

Wide-spectrum antimicrobial /1-lactam antimicrobial Macrocyclic antibiotic Antimicrobial... 

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

An attractive application of this strategy can be visualized in the synthesis of the tripeptide segment 136, Scheme 44, present in the macrocyclic antibiotic lysobactin 40, Fig. 4. It was reported that p-lactams 131 and 132, upon ring expansion under the NaOCl-TEMPO conditions indicated above, afford NCAs 133 and 134, respectively. Coupling of the NCA 133 with (S)-LeuOMe results in the formation of 135 which upon exposure to 134 provides tripeptide 136 in high overall yield [122],... 

A second period of macrocyclic chemistry was signaled by the isolation of the first macrolide antibiotic from an Actomyces culture in 1950. Brockmann and Henkel [6][7] named it picromycin (Pikromycin) (1/4), because of its bitter taste. This antibiotic contains a 14-membered ring. Since then a large number of macrocyclic lactones, lactams and cycloalkane derivatives have been discovered. Some of these compounds have a considerable physiological importance for humans and animals. Because of these physiological properties it was necessary to prepare larger quantities of these macrocylic compounds by chemical syntheses [8]. 

Antibiotics (General, Antitumor, fi-Lactam, Macrocyclic, Miscellaneous). 

Also, treatment with phenyl isothiocyanate gives no reaction, suggesting no free amine at the N-terminus. The most plausible explanation is that the N-terminus has reacted with the C-terminus to produce a cyclic amide, a lactam. (These large rings, called macrocycles, are often found in nature as hormones or antibiotics.)... 

Lactam-based synthesis of complex nucleoside antibiotics and macrocyclic peptides 00PAC1763. 

Reviews of p-lactam chemistry include the use of enolate chemistry in asymmetric synthesis <00RHA33>, the utility of 4-formyI-p-lactams as synthons in stereocontrolled syntheses <01CSR226> and the use of p-lactams in the synthesis of complex nucleoside antibiotics and macrocyclic peptides <00PACl763>. 

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