- Transannulation of Pyridotriazoles with Naphthoquinones and Indoles: Synthesis of Benzo[f]Pyrido[1,2-a]Indoles and Indolizino[3,2-b]indoles
-
Ruthenium catalysed denitrogenative transannulation of pyridotriazoles with naphthoquinones provided the transannulated benzo[f]pyrido[1,2-a]indoles derivatives in good to excellent yields. While pyridotriazoles with indoles in presence of PivOH and oxone yield indolizino[3,2-b]indoles under metal-free conditions. Quinone annulation proceeds through ruthenium-carbenoid intermediate while indole annulation may proceed via a diazo-pyridinium intermediate. Control experiments suggest that both the transformations follow the ionic mechanism. (Figure presented.).
- Rawat, Deepa,Adimurthy, Subbarayappa
-
-
- 6,11-Dioxobenzo[ f]pyrido[1,2- a]indoles Kill Mycobacterium tuberculosis by Targeting Iron-Sulfur Protein Rv0338c (IspQ), A Putative Redox Sensor
-
Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[f]pyrido[1,2-a]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of Mycobacterium tuberculosis in vitro. The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to Mycobacterium marinum. On hit expansion and investigation of the structure activity relationship, selected modifications to the dioxo moiety of the DBPI scaffold were either neutral or led to reduction or abolition of antimycobacterial activity. To find the target, DBPI-resistant mutants of M. tuberculosis Erdman were raised and characterized first microbiologically and then by whole genome sequencing. Four different mutations, all affecting highly conserved residues, were uncovered in the essential gene rv0338c (ispQ) that encodes a membrane-bound protein, named IspQ, with 2Fe-2S and 4Fe-4S centers and putative iron-sulfur-binding reductase activity. With the help of a structural model, two of the mutations were localized close to the 2Fe-2S domain in IspQ and another in transmembrane segment 3. The mutant genes were recessive to the wild type in complementation experiments and further confirmation of the hit-target relationship was obtained using a conditional knockdown mutant of rv0338c in M. tuberculosis H37Rv. More mechanistic insight was obtained from transcriptome analysis, following exposure of M. tuberculosis to two different DBPI; this revealed strong upregulation of the redox-sensitive SigK regulon and genes induced by oxidative and thiol-stress. The findings of this investigation pharmacologically validate a novel target in tubercle bacilli and open a new vista for tuberculosis drug discovery.
- Székely, Rita,Rengifo-Gonzalez, Monica,Singh, Vinayak,Riabova, Olga,Benjak, Andrej,Piton, Jérémie,Cimino, Mena,Kornobis, Etienne,Mizrahi, Valerie,Johnsson, Kai,Manina, Giulia,Makarov, Vadim,Cole, Stewart T.
-
p. 3015 - 3025
(2020/12/18)
-
- Design, synthesis and structure-activity relationship study of novel naphthoindolizine and indolizinoquinoline-5,12-dione derivatives as IDO1 inhibitors
-
Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized. The most potent compounds 5c (IC50 23 nM, IDO1 enzyme), and 5b′ (IC50 372 nM, HeLa cell) were identified as promising lead compounds.
- Yang, Rui,Chen, Yu,Pan, Liangkun,Yang, Yanyan,Zheng, Qiang,Hu, Yue,Wang, Yuxi,Zhang, Liangren,Sun, Yang,Li, Zhongjun,Meng, Xiangbao
-
p. 4886 - 4897
(2018/09/11)
-
- Copper(II)-catalyzed carbon-carbon triple bond cleavage of internal alkynes for the synthesis of annulated indolizines
-
Cleavage of C≡C bond in butynedioates via copper(II)-catalyzed reaction has been achieved, leading to the synthesis of benzo[f]pyrido[1,2-a] indole-6,11-diones in high yields by one-pot three-component reactions. In this unprecedented C≡C bond cleavage reaction of internal alkynes, both fragments from the alkyne are successively incorporated into the products.
- Sun, Jinwei,Wang, Fuyao,Hu, Huayou,Wang, Xiangshan,Wu, Hui,Liu, Yun
-
p. 3992 - 3998
(2014/05/20)
-
- Copper(II)-catalyzed synthesis of benzo[ f ]pyrido[1,2- a ]indole-6,11-dione derivatives via naphthoquinone difunctionalization reaction
-
Benzo[f]pyrido[1,2-a]indole-6,11-diones have been synthesized in high yields by copper(II)-catalyzed three-component reactions of acyl bromide, 1,4-naphthoquinone, and pyridine (or isoquinoline) via sp2-C-H difunctionalization of naphthoquinone
- Liu, Yun,Sun, Jin-Wei
-
scheme or table
p. 1191 - 1197
(2012/03/11)
-
- Microwave-assisted multicomponent synthesis of aza-, diaza-, benzo-, and dibenzofluorenedione derivatives
-
A microwave procedure was efficiently applied to the synthesis of a series of heteropolycyclic compounds with known or potential biological activities. Antitumor amide 3was obtained in a few minutes and with high yields through a solventless, one-pot cyclization, followed by treatment with the suitable amine. This method was also used to access tetracyclic aza-compounds 5/6, where their selective formation as N,N-syn and N,N-anti regioisomers was investigated under a solventless condition, or by changing the solvent, in the presence of solid supports and a catalytic amount of ecofriendly metal salts. Thermal access to similar polycyclic compounds recently reported under conventional heating by using the preformed pyridinium or isoquinolinium ylides was improved in this instance by microwave irradiation and extended to the synthesis of diaza-esters. In any case, the one-pot, three-component cyclization was more atom-efficient than the N-ylide sequence. Copyright Taylor & Francis Group, LLC.
- Defant, Andrea,Guella, Graziano,Mancini, Ines
-
p. 3003 - 3016
(2008/12/22)
-
- Synthesis and in vitro cytotoxicity evaluation of novel naphthindolizinedione derivatives
-
Novel 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-12-carboxamide derivatives and the corresponding 7,10-dihydroxy analogues were designed in accordance with Moore's and Pindur's theory and synthesized based on the structural similarity with known antitumour agents such as ellipticine, daunorubicin, mitoxantrone and 9-aminoacridine-4 carboxamide derivatives. These compounds, including structural variations of the amide side chain, were evaluated in the NCI panel of human tumour cell lines, from which 6,11-dioxo-6,11-dihydro-benzo[f]pyrido[1,2-a]indole-(2-dimethylamino-ethyl) -12-carboxamide 11a was found to be the most potent agent within the series. It showed good selectivity towards leukaemia, colon and renal cancer cell lines, with significant GI50 values, from lower than 10 nM to 0.2 μM. Moreover, its cytotoxicity against the adriamicine-resistant breast tumour cell line at a concentration lower than 1 μM turned out to be higher than the values using the clinical anticancer agents, daunorubicin and mitoxantrone.
- Defant, Andrea,Guella, Graziano,Mancini, Ines
-
p. 147 - 153
(2008/02/05)
-