RES-701-1, a novel cyclic peptide endothelin antagonist, was isolated from the culture broth of Streptomyces sp. RE-701. RES-701-1 selectively inhibited the ET-1 binding to type B endothelin receptor (ET_B receptor) with an IC₅₀ of 10 nM expressed in CHO cells and blocked the ET-1-induced elevation of intracellular free Ca²⁺ concentration in ET_B receptor-expressing COS-7 cells. Characterization of producing strain, fermentation, isolation, structure, physico-chemical and biological properties of RES-701-1 are described.

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The structure of RES-701-1, a novel microbial endothelin type B receptor antagonist, was determined. Protein chemical data and FAB-MS have identified RES-701-1 to be a cyclic polypeptide consisting of 16 common L-amino acids. This compound is so stable against proteolysis that its enzymatic digestion under standard conditions proved to be very difficult. Therefore, the primary sequence of RES-701-1 was determined by the application of advanced protein chemical methods to be Gly¹-Asn²-Trp³-His⁴-Gly⁵-Thr⁶-Ala⁷-Pro⁸-Asp^9-Trp¹⁰-Phe¹¹-Phe¹²- Asn¹³-Tyr¹⁴-Tyr¹⁵-Trp¹⁶. The compound is cyclized between the β-carboxyl group of Asp⁹ and the α-amino group of Gly¹.

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In the course of screening with the mixed lymphocyte reaction, a new inhibitor of protein kinase C with immunosuppressive activity was isolated from the fermentation broth and mycelia of Streptomyces sp. AB 1869R-359. Although certain similarities exist, this strain is morphologically and physiologically distinct from other reported producers of staurosporine-related compounds. We have found that this strain produces relatively high levels of staurosporine and the new minor compound MLR-52, which possesses the indolo[2, 3-a]carbazole chromophore of staurosporine, but differs in the substitution pattern of the sugar moiety. Their structures have been elucidated by mass and NMR spectra. MLR-52 has been shown to inhibit the enzymatic activity of protein kinase C and the murine mixed lymphocyte reaction.

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BE-23372M, a novel protein tyrosine kinase inhibitor, was isolated from the culture broth of a fungus. The producing strain, F23372, was identified as Rhizoctonia solani, based on the cultural and morphological characteristics. The active principle was extracted from the mycelium with acetone and purified by solvent extraction, silica gel column chromatography and Sephadex LH-20 column chromatography.
BE-23372M showed strong inhibitory activity against EGF receptor kinase with IC₅₀ values of 0.02 and 0.03 μm on two different substrates, whereas IC₅₀ values against protein kinase C and cAMP-dependent protein kinase were 4.5 and >20μM, respectively. The compound inhibited the growth of A431 human epidermoid carcinoma and MKN-7 human stomach cancer cell lines with IC₅₀ values of 8 and 24μM, respecitvely.

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BE-23372M, a new protein tyrosine kinase inhibitor, has been obtained as a reddish orange solid. The compound, C₁₇H₁₂O₆, HRFAB-MS: m/z 312.0625 (M)⁺, is an acidic substance, showing UV (MeOH)λ_max (ε) 266 (8, 800), 426 nm (20, 400), and IR (KBr)ν_max 1752(C=O) and 3298(OH) cm^-1. The structure of BE-23372M, (E)-3-(3, 4-dihydroxybenzylidene)-5-(3, 4-dihydroxyphenyl)-2(3H)-furanone, has been elucidated by ¹H and ¹³C NMR studies.

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In a preceding paper, the physico-chemical properties and structural elucidation of BE-23372M, a potent novel protein tyrosine kinase inhibitor, were described. In this paper, we report the synthesis of BE-23372M from 3-(3, 4-dimethoxybenzoyl)propionic acid and veratraldehyde or 3, 4-diacetoxy-benzaldehyde. The structure of BE-23372M was confirmed to be (E)-3-(3, 4-dihydroxybenzylidene)-5-(3, 4-dihydroxyphenyl)-2(3H)-furanone.

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A novel antitumor bicyclic depsipeptide, FR901228, was isolated from a broth culture of Chromobacterium violaceum No. 968 as colorless prisms and the molecular formula was determined as C₂₄H₃₆N₄O₆S₂. This antibiotic reverted the transformed morphology of a Ha-ras transformant to normal, and exhibited prominent antitumor activities against murine and human tumor cell lines both in vitro and in vivo.

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The structure of FR901228 (C₂₄H₃₆N₄O₆S₂), including stereochemical details, was determined by a combination of spectroscopic, chemical evidence and single-crystal X-ray crystallographic analysis using anomalous dispersion from the S atoms.

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The antitumor activities of FR901228, (E)-(1S, 4S, 10S, 2R)-7-[(Z)-ethylidene]-4, 21 -diisopro-pyl-2-oxa-12, 13-dithia-5, 8, 20, 23-tetraazabicyclo[8, 7, 6]-tricos-16-ene-3, 6, 9, 19, 22-pentanone, isolated from Chromobacterium violaceum No. 968, were studied in animals. FR901228 (ip) prolonged the life of mice bearing such murine ascitic tumors as P388 and L1210 leukemias and B16 melanoma, and inhibited (iv) the growth of murine solid tumors (Colon 38 carcinoma, M5076 reticulum cell sarcoma and Meth A fibrosarcoma) and human solid tumors (Lu-65 and LC-6 lung carcinomas, and SC-6 stomach adenocarcinoma) implanted in normal and nude mice, respectively. Its antitumor activity was especially potent against murine Meth A fibrosarcoma and human SC-6 stomach adenocarcinoma which were refractory to mitomycin C or cisplatin. FR901228 also was more effective against mitomycin C-, cyclophosphamide-, vincristine-and 5-fluorouracil-resistant P388 leukemias than against non-resistant P388 in mice. These res ts suggest that FR901228 will be a new type of drug for the treatment of cancer.

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Three new manumycin class antibiotics, namely manumycins E, F and G, were isolated from the culture broth of Streptomyces sp. strain WB-8376. Their structures were established by spectroscopic methods, and the S configuration of C-4 in the epoxycyclohexenone moiety was determined by CD exciton chirality method for each of the three compounds. Manumycins E, F and G are active against Gram-positive bacteria, and have moderate inhibitory effects on the farnesylation of p21 ras protein. They demonstrated weak cytotoxic activity against human colon tumor cell HCT-116.

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A new glycopeptide antibiotic, balhimycin, has been isolated from the fermentation broth of a Amycolatopsis sp. Y-86, 21022. Balhimycin belongs to the vancomycin class of glycopeptides and contains a dehydrovancosamine sugar. The biological activity of balhimycin has been compared extensively with that of vancomycin against methicillin resistant staphylococci and also against anaerobes. Balhimycin is marginally superior to vancomycin in its in vitro activity against anaerobes and in its bactericidal properties.

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Two related antibiotics, 167-A and 167-B, were isolated from the fermentation broth of a mutant of an inactive wild strain of Amycolata autotrophica. Antibiotic 167-B was found to be cervinomycin A₂; antibiotic 167-A is a new representative of the same group and has the structure of 18-O-demethyl cervinomycin A₂.

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A series of the novel oleandomycin 9-oximes has been prepared and characterized by spectroscopic data and X-ray analysis. The antibacterial in vitro activities of the oximes (6-10) were compared with that of oleandomycin (1). Among the novel derivatives the most active compound was 8(R)-rriethyloleandomycin-9-oxime (9) in contrast to its 8(S)-isomer (10) which possessed only low potency. Some preliminary pharmacokinetic data of 9 confirmed its activity. Compound 9 has been advanced to further biological study.

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A series of new penems (4-17), having a bicyclic imidazole moiety as the C-2 substituent, has been synthesized. The antimicrobial activity of these compounds and their susceptibility to renal dehydropeptidase-1 (DHP-1) are elucidated, and their structure-activity relationships are discussed.

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