The sponge Agelas oroides contains 4,5-dibromopyrrole-2-carboxylic acid (4), the corresponding nitrile and amide; oroidin contains an amide derived from (4) and a substituted 2-aminoimidazole.

Abstract

The esperamicins represent a class of antitumor antibiotics characterized by an unusual chemical core structure and extremely potent cytotoxicity. The mechanism by which these drugs produce cytotoxicity was investigated and found to be related to the formation of single-and doublestrand DNA breaks. Using five structurally related analogs, we defmed a structure-activity relationship for cytotoxicity in various eukaryotic and DNA-repair-deficient prokaryotic cell lines, for DNA breakage in a human colon carcinoma cell line, and for DNA breakage in vitro in pBR322 DNA. Mild reducing agents such as dithiothreitol greatly increased the DNA breakage potency of these analogs in vitro. Results suggest that the pendant aromatic chromophore of esperamicin A1 may contribute to the uptake of the drug into cells but may also hinder double-strand DNA break formation. Little DNA breakage specificity was observed for the drug in a 139-base-pair fragment of pBR322 DNA. Evidence supports a previously proposed mechanism whereby esperamicins may produce the observed DNA breaks through reduction of the methyl trisulfide group to a thiolate anion followed by a Michael addition of the anion across the a,4-unsaturated ketone. This addition may result in the saturation of the bridgehead double bond, thus allowing the two triple bonds to approach each other, causing cyclization of the diyn-ene to form a phenylene diradical. It is likely that this diradical is the active form of the drug responsible for single-and double-strand DNA breakage produced by this class of antitumor agents.A family of extremely potent compounds showing broad spectrum antimicrobial and antitumor activity in murine systems has been identified in cultures of Actinomadura verrucosospora (1). The elucidation of their complex chemical structures has recently been reported (2,3). This class of compounds, collectively called the esperamicins, is characterized by the presence of a central core containing a number of unusual features. These include a bicyclo[7.3.1] ring system, an allylic trisulfide attached to the bridging atom, a 1,5-diyn-3-ene as part of the ring system, and an a,3-unsaturated ketone in which the double bond is at the bridgehead of the bicyclic system. Esperamicin A1 (espA) contains four sugars attached to the bicyclic core and an aromatic chromophore attached to one of the sugars (3), as shown in Fig. 1A.Various analogs of espA have been prepared by chemical hydrolysis, including esperamicin C (espC), which lacks both the 2-deoxy-L-fucose and the aromatic ring moieties; esperamicin D (espD), which is similar to espC but also lacks the thiomethyl hexopyranose moiety; esperamicin E (espE), which consists of the bicyclic core and the hydroxylamino sugar; esperamicin Z (espZ), which is an esperamicin A1 that has undergone reductive cyclization of the trisulfide and subsequent aromatization of the 1,5-diyn-3-ene structure; and esperamicin X (espX), which is an analog of espZ but lacking the trisaccharide at the C-12 position (see Fig. 1A). The stru...

No abstract

A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.