Tetracyclic Indole Research Articles

Atom-Economic Synthesis of Pentaleno[2,1-b]indoles via Tandem Cyclization of Alkynones Initiated by Aminopalladation.

An atom-economic Pd(OAc)2-catalyzed tandem cyclization of alkynones to synthesize pentaleno[2,1-b]indoles was developed efficiently. In the formed tetracyclic indole framework, two neighboring stereocenters, one being all-carbon quaternary, are being constructed in a single process with excellent diastereoselectivity. This reaction was initiated by aminopalladation of alkynes and quenched by addition to the intramolecular carbonyl groups.

Enantioselective total synthesis of (+)-arborescidine C and related tetracyclic indole alkaloids using organocatalysis.

A concise and enantioselective synthesis of the tetracyclic indoles, including the naturally occurring compounds (+)-arborescidine C and (+)-arborescidine B, was achieved by the key step of Pictet-Spengler cyclization reaction with a Jacobsen-type thiourea organocatalyst. The synthetic process was further demonstrated in a pot-economy strategy and was achieved in a one-pot operation.

Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication.

We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2β, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2β, concentrations greater than those needed to inhibit HIV-1 replication were required to elicit significant alterations. Thus, the ability of 1C8 to alter the SRSF10-dependent splicing of HIV-1 transcripts, with minor effects on cellular splicing, supports the view that SRSF10 may be used as a target for the development of new anti-viral agents.

Discovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Polymorphisms.

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.

Tetracyclic indole alkaloids with antinematode activity from Uncaria rhynchophylla

A new tetracyclic indole alkaloid, 17-O-methyl-3,4,5,6-tetradehydrogeissoschizine, together with seven known ones, were isolated from the aerial part of Uncaria rhynchophylla. Their structures were unambiguously elucidated by spectroscopic methods and comparing with the literature data. Among them, compounds 1, 3, 4 and 6–8 showed potent to moderate antinematode activities against Panagrellus redivevus at a concentration of 250 μg/mL.

Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants.

The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).

ChemInform Abstract: Building Polycyclic Indole Scaffolds via Gold(I)‐Catalyzed Intra‐ and Inter‐Molecular Cyclization Reactions of 1,6‐Enynes.

Abstract A gold(I) catalyzed cycloisomerization of indolyl-1,6-enynes via 5- exo -dig cyclization is reported. The reaction passes through an intermediate whose fate can be steered to yield different indole polycyclic scaffolds through various intra- and inter-molecular cyclization reactions. One of the key transformations of indolyl-1,6-enynes was a formal [2+2+2] cycloaddition reaction with various aldehydes to afford natural product-like tetracyclic indoles.

Substituted tetracyclic indole core derivatives of HCV NS5A inhibitor MK-8742

As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.

Alternative core development around the tetracyclic indole class of HCV NS5A inhibitors

Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.

Matched and mixed cap derivatives in the tetracyclic indole class of HCV NS5A inhibitors

A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.

Total synthesis of the tetracyclic indole alkaloid ht-13-A

Total synthesis of the tetracyclic indole alkaloid ht-13-A is reported starting ultimately from commercially available (−)-4-amino-2-hydroxybutyric acid. The key steps in this synthesis are a Lewis acid mediated acyliminium ion allylation, a Mitsunobu reaction, a palladium catalyzed Stille-Kelly intramolecular cross coupling, and a carbon monoxide mediated palladium catalyzed reductive N-heterocyclization.

Building polycyclic indole scaffolds via gold(I)-catalyzed intra- and inter-molecular cyclization reactions of 1,6-enynes

A gold(I) catalyzed cycloisomerization of indolyl-1,6-enynes via 5-exo-dig cyclization is reported. The reaction passes through an intermediate whose fate can be steered to yield different indole polycyclic scaffolds through various intra- and inter-molecular cyclization reactions. One of the key transformations of indolyl-1,6-enynes was a formal [2+2+2] cycloaddition reaction with various aldehydes to afford natural product-like tetracyclic indoles.

A Parallel Synthesis Approach to the Identification of Novel Diheteroarylamide-Based Compounds Blocking HIV Replication: Potential Inhibitors of HIV-1 Pre-mRNA Alternative Splicing.

A 256-compound library was evaluated in an anti-HIV screen to identify structural "mimics" of the fused tetracyclic indole compound 1 (IDC16) that conserve its anti-HIV activity without associated cytotoxicity. Four diheteroarylamide-type compounds, containing a common 5-nitroisobenzothiazole motif, were identified as active. In subsequent screens, the most potent compound 9 (1C8) was active against wild-type HIV-1IIIB (subtype B, X4-tropic) and HIV-1 97USSN54 (subtype A, R5-tropic) with EC50's of 0.6 and 0.9 μM, respectively. Compound 9 also inhibited HIV strains resistant to drugs targeting HIV reverse transcriptase, protease, integrase, and coreceptor CCR5 with EC50's ranging from 0.9 to 1.5 μM. The CC50 value obtained in a cytotoxicity assay for compound 9 was >100 μM, corresponding to a therapeutic index (CC50/EC50) of approximately 100. Further comparison studies revealed that, whereas the anti-HIV activity for compound 9 and the parent molecule 1 are similar, the cytotoxic effect for compound 9 was, as planned, markedly suppressed.

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis.

Corynantheine alkaloids with a tetracyclic indole[2,3-a]-quinolizidine motif are an important issue in academia and in the life science industries due to their broad bioactivity profile. In particular, the main biological effects described for indoloquinolizidines include analgesic, anti-inflammatory, antihypertensive, and antiarrhythmic activities, as well as inhibition of multiple ion channels, affinity for opioid receptors, and activity against Leishmania. For that reason, in the last decades, numerous efforts have been invested in the development of novel synthetic strategies to obtain the indole[2,3-a]-quinolizidine system. This review focuses on the synthetic methodologies developed to target the most important alkaloids of this family, and highlights the potential use of these alkaloids or analogs to treat several diseases, ranging from cancer to neurodegenerative disorders.

Total synthesis of the tetracyclic indole alkaloid ht-13-B.

An expedient synthesis corroborating the proposed structure of the tetracyclic indole alkaloid ht-13-B is presented. Key synthetic steps include acyliminium ion allylation, a Mitsunobu reaction, a palladium-catalyzed Stille-Kelly cross coupling reaction, and a carbon monoxide-mediated palladium-catalyzed reductive N-heterocyclization. The chiral centers are ultimately derived from commercially available trans-4-hydroxy-l-proline.

ChemInform Abstract: Tandem C‐3/C‐2 Annulation of Indole, Benzofuran, and Benzothiophene with 2‐Alkynyl Benzylalcohol: An Efficient Approach to the Diverse Tetracyclic Heteroazulene Ring Systems.

AbstractThe flexible and versatile strategy offers access to biologically and pharmaceutically relevant tetracyclic indole, benzofuran and benzothiophene derivatives bearing aryl, hetaryl and alkyl substituent on the azulene ring.

Tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can specifically target bacterial DNA ligases and can distinguish them from human DNA ligase I.

DNA ligases are critical components for DNA metabolism in all organisms. NAD(+)-dependent DNA ligases (LigA) found exclusively in bacteria and certain entomopoxviruses are drawing increasing attention as therapeutic targets as they differ in their cofactor requirement from ATP-dependent eukaryotic homologs. Due to the similarities in the cofactor binding sites of the two classes of DNA ligases, it is necessary to find determinants that can distinguish between them for the exploitation of LigA as an anti-bacterial target. In the present endeavour, we have synthesized and evaluated a series of tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives for their ability to distinguish between bacterial and human DNA ligases. The in vivo inhibition assays that employed LigA deficient E. coli GR501 and S. typhimurium LT2 bacterial strains, rescued by ATP-dependent T4 DNA ligase or Mycobacterium tuberculosis NAD(+)-dependent DNA ligase (Mtb LigA), respectively, showed that the compounds can specifically inhibit bacterial LigA. The in vitro enzyme inhibition assays using purified MtbLigA, human DNA ligase I & T4 DNA ligase showed specific inhibition of MtbLigA at low micromolar range. Our results demonstrate that tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can distinguish between bacterial and human DNA ligases by ∼5-folds. In silico docking and enzyme inhibition assays identified that the compounds bind to the cofactor binding site and compete with the cofactor. Ethidium bromide displacement and gel-shift assays showed that the inhibitors do not exhibit any unwanted general interactions with the substrate DNA. These results set the stage for the detailed exploration of this compound class for development as antibacterials.

ChemInform Abstract: Molecular Iodine‐Mediated Cascade Reaction of 2‐Alkynylbenzaldehyde and Indole: An Easy Access to Tetracyclic Indoloazulene Derivatives.

AbstractThe synthesis of iodo‐substituted tetracyclic indole fused azulene derivatives is achieved by reaction of various phenylethynyl benzaldehydes and different indoles in the presence of molecular iodine.

Molecular Iodine‐Mediated Cascade Reaction of 2‐Alkynylbenzaldehyde and Indole: An Easy Access to Tetracyclic Indoloazulene Derivatives

AbstractThe synthesis of iodo‐substituted tetracyclic indole fused azulene derivatives was achieved from the reaction of 2‐(substituted phenylethynyl)benzaldehydes and different indoles in the presence of molecular iodine. The reaction involves the formation of a bisindole from the corresponding 2‐(substituted phenylethynyl)benzaldehyde and indole followed by iodocyclization in a one‐pot cascade process. A wide range of 2‐(substituted phenylethynyl)benzaldehydes and indoles were utilized in this protocol to derive a diverse range of iodo‐substituted tetracyclic indole fused azulene derivatives in moderate to good yields. Further functionalizations of the iodo‐substituted tetracyclic indole fused azulenes were achieved by various palladium‐catalyzed cross‐coupling reactions to generate highly substituted tetracyclic indole fused azulene derivatives.magnified image

Facile synthesis of thiochromeno[2,3-b]indol-11(6H)-ones and pyrido[3′,2′:5,6]thiopyrano[2,3-b]indol-5(10H)-ones

Abstract Indole-2(3H)thiones were cyclized under the action of 2-fluorobenzoyl chlorides to give thiochromeno[2,3-b]indol-11(6H)-ones or under the action of 2-chloronicotinoyl chlorides to give pyrido[3′,2′:5,6]thiopyrano[2,3-b]indol-5(10H)-ones. The reaction of cyclization proceeds regioselectively in DMF and does not require transition metals for completion. Obtained heterocycles are isosteric analogues of various tetracyclic indole derived alkaloids.