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Streptonigrin (STN, 1) is a highly functionalized aminoquinone alkaloid with broad and potent antitumor activity. Here, we reported the biosynthetic gene cluster of STN identified by genome scanning of a STN producer Streptomyces flocculus CGMCC4.1223. This cluster consists of 48 genes determined by a series of gene inactivations. On the basis of the structures of intermediates and shunt products accumulated from five specific gene inactivation mutants and feeding experiments, the biosynthetic pathway was proposed, and the sequence of tailoring steps was preliminarily determined. In this pathway, a cryptic methylation of lavendamycin was genetically and biochemically characterized to be catalyzed by a leucine carboxyl methyltransferase StnF2. A [2Fe-2S](2+) cluster-containing aromatic ring dioxygenase StnB1/B2 system was biochemically characterized to catalyze a regiospecific cleavage of the N-C8' bond of the indole ring of the methyl ester of lavendamycin. This work provides opportunities to illuminate the enzymology of novel reactions involved in this pathway and to create, using genetic and chemo-enzymatic methods, new streptonigrinoid analogues as potential therapeutic agents.

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2′, C-3′ and C-11′ positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.

A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.

Quinoline 12 was obtained by a Friedlander reaction from 2-aminobenzaldehyde and methyl acetoacetate. Reduction, silylation then oxidation provided compound 8a. A Pictet–Spengler reaction between the latter and tryptophan methyl ester yielded compound 14, then compound 7 by desilylation. Numerous attempts to prepare a cyclized derivative of this analogue of lavendamycin 7 by conventional ways failed. Fortunately, a good result was obtained via a hemiaminal intermediate and compound 21 was thus obtained in satisfactory yield. A conjugate addition occurred in the course of its reduction which led to compound 22. Biological tests were carried out with compound 7 and the conformationally restricted analogues 21 and 22.

Novel lavendamycins including two water soluble derivatives were synthesized via short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptophans produced lavendamycin esters or amides 11-17. Lavendamycins 18-21 were obtained, respectively, by further transformations of 13-15 and 17. Several lavendamycins were found to be potent HIV reverse transcriptase inhibitors with very low toxicity in vitro and in vivo. Several compounds also acted either additively or synergistically to inhibit enzyme activity together with AZT-triphosphate.

A series of 7-amino- and 7-acetamidoquinoline-5,8-diones with aryl substituents at the 2-position were synthesized, characterized, and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1) -directed antitumor agents. The synthesis of lavendamycin analogues is illustrated. Metabolism studies demonstrated that 7-amino analogues were generally better substrates for NQO1 than 7-amido analogues, as were compounds with smaller heteroaromatic substituents at the C-2 position. Surprisingly, only two compounds, 7-acetamido-2-(8'-quinolinyl)quinoline-5,8-dione (11) and 7-amino-2-(2-pyridinyl)quinoline-5,8-dione (23), showed selective cytotoxicity toward the NQO1-expressing MDA468-NQ16 breast cancer cells versus the NQO1-null MDA468-WT cells. For all other compounds, NQO1 protected against quinoline-5,8-dione cytotoxicity. Compound 22 showed potent activity against human breast cancer cells expressing or not expressing NQO1, with respective IC50 values of 190 nM and 140 nM and a low NQO1-mediated reduction rate, which suggests that the mode of action of 22 differs from that of lavendamycin and involves an unidentified target(s).

The synthesis of the CD ring system of Streptonigrin and Lavendamycin alkaloid analogues by cross-coupling under Suzuki's conditions has been studied. Steric hindrance is the main problem. It has been solved either by using strong bases or working in a sealed tube under pressure.

An efficient route to a key intermediate in the synthesis of lavendamycin from a suitably substituted 2-chloroquino-line derivative via aminocarbonylation with tryptophan methyl ester as nucleophile, is reported.

A convergent synthesis of streptonigrin and lavendamycin analogues incorporating a quinoline-5,8-dione structure is reported. The approach is based on our synthetic methodology which involves such reactions as metalation, heteroring cross-coupling and oxidative demethylation.

Novel cytocidal compounds designated oxopropalines A, B, D, E and G were isolated from the fermentation of an actinomycete named Streptomyces sp. G324, a strain that also produced an antitumor antibiotic, lavendamycin. All these compounds possessed a beta-carboline chromophore. The structures of the oxopropalines were elucidated by several NMR spectral analyses and other spectroscopic experiments.

Aza-Wittig reaction of iminophosphorane 3, derived from ethyl a-azido-β-(3-indolyl) propenoate and tri-phenylphosphine, with 2-formylpyrrole and 2-formylquinolines leads to Eudistomins A and M and Lavendamycin derivatives respectively.

A convergent synthesis of streptonigrin and lavendamycin analogues incorporating a quinoline-5,8-dione structure is reported. The approach is based on our synthetic methodology which involves such reactions as metalation, heteroring cross-coupling and oxidative demethylation.

An efficient route to a key intermediate in the synthesis of lavendamycin from a suitably substituted 2-chloroquinoline derivative via aminocarbonylation with tryptophan methyl ester as nucleophile, is reported.

Aza-Wittig reaction of iminophosphorane 3, derived from ethyl a-azido-β-(3-indolyl) propenoate and tri-phenylphosphine, with 2-formylpyrrole and 2-formylquinolines leads to Eudistomins A and M and Lavendamycin derivatives respectively.

ABC analogues of the antitumor antibiotic lavendamycin, which contain the key metal chelation site and redox-active quinone unit essential for biological activity, were prepared via the palladium(0)-catalyzed cross-coupling reaction of various 2-haloheteroaromatics with 2-stannylated pyridines and quinolines. Using the Stille reaction, 2-bromo substituted quinolines and 1-bromoisoquinolines were found to undergo efficient coupling with 2-pyridinylstannanes to provide unsymmetrical heterobiaryl derivatives. While the Stille reaction using the reverse coupling partners (i.e., 2-quinolinylstannanes and haloheteroaromatics) had not received much attention in the literature, we found that this alternative coupling reaction efficiently provided several new heterobiaryl derivatives. The gold-catalyzed intramolecular cycloisomerization of N-(prop-2-ynyl)-1H-indole-2-carboxamide smoothly afforded a beta-carbolinone derivative that was subsequently used for a Pd(0)-catalyzed cross-coupling directed toward the synthesis of lavendamycin analogues.

A series of N-propargylindole-2-carboxamides were found to undergo a AuCl 3-catalyzed cycloisomerization to give beta-carbolinones in high yield. The corresponding beta-chlorocarboline derivative was prepared and used for Pd(0)-catalyzed cross-coupling chemistry directed toward the synthesis of lavendamycin analogues.

A series of 7-N-acyllavendamycins with zero, one or two substituents at the C-2', C-3', and C-11' were synthesized through short and efficient methods. Pictet-Spengler condensation of 7-N-acylamino-2-formylquinoline-5,8-diones with tryptamine or tryptophans produced the desired lavendamycins. Screening data on a panel of three ras oncogene-transformed cell lines and the non-transformed parent cell line showed that a significant number of these analogues are potent antitumor agents and appear to be particularly active against K-ras transformed cells. Compared with the corresponding quinolinediones, these novel lavendamycins are much more inhibitory toward the transformed cells indicating that the beta-carboline moiety of the lavendamycin analogues plays an important role in its potency and selective toxicity.

The naphthoquinone skeleton is found in many natural products and has been employed as a synthetic intermediate for the preparation of numerous heterocyclic compounds with interesting biological properties such as antitumor, antibacterial, antifungal and antiinflammatory agents. The quinone core of streptonigrin and lavendamycin has been proposed to be a determining factor in their antitumor activity. Recently, the linearly substituted quinolinediones have revealed the importance of the quinone framework for potent antitumor activity against the cell lines. Furthermore, Cheng et al. designed the fused benzofuroquinone that possesses a characteristic “2-phenylnaphthalene-type” structural framework in which the two rings are coplanar. They found that the designed benzo[b]naphtho[2,3-d]furan6,11-dione derivatives exhibited strong inhibitory activity throughout the entire series of cancer cell lines. A decade ago, dinaphtho[1,2-b;2',3'-d]furan-7,12-dione 3 was isolated from stems of Paulownia tomentos, a perennial tree widely distributed in China, Japan, and Korea. The naphthofuroquinone 3 significantly reduced viral cytopathic effect in a standard in vitro antiviral assay with HeLa cells. It is also interesting that this structural pattern is commonly observed in other biologically active compounds including camptothecin, ellipticine, and mappicine, a class of DNA Topoisomerase-I (Topo-I) inhibitors that exhibit efficious antitumor activity. Here, we would like to report the synthesis of naphthofuroquinone derivatives, and their DNA TopoI inhibition and cytotoxicity against various cancer cell lines.

Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.

A five-step approach to the preparation of the β-carboline CDE ring system of lavendamycin is detailed and is based on: (1) thermal cycloaddition of 3,5,6-tricarbomethoxy-1,2,4-triazine with the pyrrolidine enamine of o-bromopropiophenone followed by (2) implementation of a newly developed palladium (O) mediated β-carboline synthesis.

Cycloaddition de Diels Alder de triazine-1,2,4 tricarboxylate de triethyle avec des enamines conduit aux aryl-4 pyridinetricarboxylates-2,3,6 de triethyle; le methyl-4 β-carbolinedicarboxylate-1,3 de dimethyle est ensuite obtenu par cyclisation en presence d'un complexe de Pd(0) de l'amino-3 bromo-2' phenyl-4 methyl-5 pyridinedicarboxylate-2,6. Preparation des amino-7 et amino-7 [pyridyl-2]-2 quinoleinequinones-5,8

A regiospecific and convergent synthesis of Lavendamycin (1) starting from 8-hydroxyquinoline and indole via Bischler-Napieralski cyclisation is described.

Synthese basee sur la condensation de Friedlander de l'amino-2 benzyloxy-3 bromo-4 benzaldehyde et d'acetyl-1 methyl-4 β-carbolinecarboxylate-3 de methyle prepare a partir d'amino-3 bromo-2' phenyl-4 methyl-5 pyridinedicarboxylate-2,6 de dimethyle via la cyclisation en presence de complexe de Pd(0) de l'acetyl-6 amino-5 bromo-2' phenyl-4 methyl-3 picolinate de methyle

The structure elucidation of lavendamycin (1a), a new antitumor antibiotic related to streptonigrin (2) is described. The NMR spectra of 1a and several model compounds 3,4 < and 5a-b are also discussed.

The preparation of 7-amino-2-(2′-pyridyl)quinoline-5,8-quinone-6′-carboxylic acid (4) constituting a potential minimum, potent pharmacophore of streptonigrin (1) and lavendamycin (2), two structurally-related naturally-occurring antitumor-antibiotic, is detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C-6′ acid potentiates the antitumor, antimicrobial, and cytotoxic activity of the naturally-occurring, substituted 7-aminoquinoline-5,8-quinone AB ring systems, the C-6′ carboxylic acid of 4 diminishes the observed antimicrobial and cytotoxic properties of 7-amino-2-(2′-pyridyl)quinoline-5,8-quinone.

Intermediary products in the synthesis of lavendamycin were tested for mutagenic activities in Salmonella typhimurium TA 98 and TA 100 with and without a metabolic activation system. Lavendamycin analogs having a methyl group at the 3' position showed a significant mutagenicity to TA 100 after the metabolic activation using S9 mix prepared from rat liver homogenate. Oxidative products of the 8-hydroxyguinoline derivatives were mutagenic without the metabolic activation. Of these oxidative products, desamino-desmethyllavendamycin methyl ester was identified as a metabolic product obtained by the incubation of the 8-hydroxyguinoline derivative with mouse liver homogenate.

The total synthesis of the methyl ester of the antibiotic lavendamycin (4a) by an 8-step sequence from 8-methoxyquinaldic acid (6) is described.

Synthese a partir de l'ester de methyle du tryptophane et de benzyloxy-8 quinoleinecarbaldehyde-2 via l'oxydation du [dibromo-5,7 hydroxy-8 quinolyl-2]-1 β-carbolinecarboxylate-3 de methyle

Synthese de l'[hydroxy-8 quinolyl-2]-1 methyl-4 β-carbolinecarboxylate-3 d'ethyle (A) par reaction de Pictet Spengler de benzyloxy-8 quinoleinecarbaldehyde-2 et de β-methyl tryptophanate d'ethyle suivie d'hydrogenolyse; a partir de A par l'intermediaire de bromation puis d'oxydation, obtention des esters d'ethyle et de methyle de l'acide [bromo-7 dihydro-5,8 dioxo-5,8 quinolyl-2]-1 methyl-4 β-carbolinecarboxylique-3; l'ester de methyle a deja ete transforme en ester de methyle de lavendamycine

The preparation and evaluation of 7-amino-5,8-dioxo-2-(2'-pyridyl)quinoline-6'-carboxylic acid (5a) and 7-amino-2-(2'-aminophenyl)-5,8-dioxoquinoline-5'-carboxylic acid (6a) constituting potential minimum, potent pharmacophores of streptonigrin (1a) and lavendamycin (2a), two structurally related naturally occurring antitumor antibiotics, are detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C-ring C-6' carboxylic acid potentiates the antitumor, antimicrobial, and cytotoxic properties of the naturally occurring, substituted 7-aminoquinoline-5,8-dione AB ring systems, the C-6'/C-5' carboxylic acid of 5a/6a diminishes the observed antimicrobial and cytotoxic properties of the 2-(2'-pyridyl)- and 2-(2'-aminophenyl)-7-aminoquinoline-5,8-diones. A direct comparison of the antimicrobial and cytotoxic properties of a complete set of streptonigrin and lavendamycin partial structures is detailed in efforts to define the role peripheral substituents play in potentiating the biological properties of the naturally occurring and synthetic agents bearing the 7-aminoquinoline-5,8-dione AB ring system and in efforts to define the minimum, potent pharmacophore of the naturally occurring antitumor antibiotics. The relationship of these observations to a chemical mechanism of cellular toxicity is discussed.

Etude de la synthese de R-2 amino-7 methoxy-6 quinoleinequinone-5,8 (R=H ou pyridyl-2) par substitution nucleophile en 6 de bromo-7 R-2 quinoleinequinone-5,8 suivie d'action de NaN 3 /Na 2 S 2 O 4