Synthesis of 5-deazathiogirollines: analogs of a natural antitumor agent

Schiavi, Bruno; Ahond, A.; Al‐Mourabit, Ali; Poupat, C.; Chiaroni, A.; Gaspard, Christiane; Potìer, Pierre

doi:10.1016/s0040-4020(02)00383-6

Cited by 22 publications

(15 citation statements)

References 9 publications

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“…Commercially available compound 5 was lithiated using lithium diisopropyl amide (LDA) followed by reaction with aldehydes to afford 6a–o in yields ranging from 9% to 81% (Scheme 2). 36 Compounds 6a–l and 6o were converted to 7a–l and 7o by reduction of secondary alcohols and deprotection of t -butoxycarbonyl (Boc) with triethylsilane and trifluoroacetic acid (TFA), respectively, in yields ranging from 14% to 88%. 22 Compounds 7m and 7n were prepared by simultaneous reduction of the hydroxyl group and removal of the Boc protective group of 6m and 6n using hydriodic acid in 10% and 43% yields, respectively.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

Ishita

Stefanopoulos

Khalil

et al. 2018

Bioorganic & Medicinal Chemistry

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The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthalenylmethyl)-2-thiazolyl]cyclohexanecarboxamide (41F5), a fungistatic agent previously identified through phenotypic screening (Antimicrob Agents Chemother. 2013;57:4349). Modifications to improve potency and water-solubility of 41F5 focused primarily on the 5-naphthalenyl group, the thiazole core, and the methylene linker between these two structural elements. In general, compounds with lipophilic [5+6] bicyclic ring systems, such as the 7-benzothiophenyl- and 4-indanyl groups, at the 5-position were 2-3 times more active against both fungal species as compared to 41F5. Also, introduction of a carbonyl group at the methylene linker of 41F5 resulted in a 2-3-fold increase in potency. These highly active compounds also showed generally low toxicities against murine P388D1 macrophages resulting in selectivity indices ranging from 63 to >200. Compounds that were highly active against fluconazole-sensitive C. neoformans strains had almost identical activity against fluconazole-resistant variants of this fungus indicating that 14α-demethylase is not their molecular target. Highly active compounds also retained activity against H. capsulatum phagocytosed into P388D1 macrophages.

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

Ishita

Stefanopoulos

Khalil

et al. 2018

Bioorganic & Medicinal Chemistry

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“…Bischlorination by treatment of diol 23 with NCS and PPh 3 followed by deprotection of the TIPS ether with TBAF, gave 24 in 65% yield over two steps. 13 Oxidation of alcohol 24 with TEMPO and PhI(OAc) 2 afforded the key fragment 5 in 81% yield.…”

Section: Resultsmentioning

confidence: 99%

Enantioselective total synthesis of atpenin A5

et al. 2009

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Enantioselective total synthesis of atpenin A5, a potent mitochondrial complex II (succinate-ubiquinone oxidoreductase) inhibitor, has been achieved by a convergent approach through a coupling reaction between 5-iodo-2,3,4,6-tetraalkoxypyridine and a side-chain aldehyde. The two key segments were synthesized through ortho-metalation/boronation with (MeO) 3 B/oxidation with mCPBA, ortho-iodination, halogen dance reaction, Sharpless epoxidation and regioselective epoxide-opening reaction. This synthetic study resulted in the revision of the earlier reported 1 H-NMR data of the natural atpenin A5 and the confirmation of the stereochemical assignment.

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“…The molecular weight of girolline is 262 g/mol and that of hymenialdisine is 324 g/mol. All other compounds are synthetic analogues of girolline: 2 5deazathiogirolline (erythro) [11], 3 5-deazathiogirolline (threo) [11], 4 (+)-(3S,4R)-3-benzyloxy-4,5-O-isopropylidene-4,5-dihydroxy-1-pentene [12], 5 (2R/S,3S,4R)-3-benzyloxy-1,2-epoxy-4,5-O-isopropylidene-4,5-dihydroxypentane [12], 6 2-amino-4-[(1′S,2R′)-1′-benzyloxy-(2′,3′)-dihydroxypropyl]-thiazole-N2-tertbutylcarbamate [12], 7 2-amino-4-[(1′S,2′R)-3′-azido-1′-benzyloxy-2′-hydroxypropyl]-thiazole-N2-tert-butycarbamate [12], 8 2amino-4-[(1′S,2′S)-3′-azido-1′-benzyloxy-2′-chloropropyl]-thiazole-N2-tert-butycarbamate [11], 9 4-deazathiogirolline [12], 10 dibromocantharelline, and 11 hymenialdisine.…”

Section: Compoundsmentioning

confidence: 99%

“…The antiplasmodial activity of girolline approached that of artemisinin or chloroquine, in totally inhibiting P. falciparum growth in vitro, whatever the chloroquine sensitivity of the strain. Then, the synthesis of two series of analogues (the series of 5-deazathiogirolline and the series of 4-deazathiogirolline), that do not contain the aminoimidazole heterocycle, was undertaken but as for their antitumor activity [11], [12], they were devoid of any action. The aminoimidazole heterocyclic ring thus seems to be necessary both for the antitumor activity [6] and probably for the antiplasmodial properties.…”

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confidence: 99%

Girolline: A Potential Lead Structure For Antiplasmodial Drug Research

et al. 2008

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Girolline is a 2-aminoimidazole derivative extracted from Cymbastela cantharella (a New-Caledonian sponge) that has shown antitumor activity. In this study, we investigated its antimalarial activity and the point of action within the erythrocytic cycle of Plasmodium falciparum. Initially, we tested girolline and some synthetic analogues in vitro against four P. falciparum strains. The IC (50) values of girolline ranged from 77 to 215 nM, and as with artemisinin or chloroquine, girolline inhibited parasitic growth by 100 %. Girolline was found to be active at a dose of 1 mg/kg/d (orally and intraperitoneally) in vivo. Moreover, there was a significant synergistic effect between girolline and chloroquine in vitro. The investigation of the mechanism of action of girolline during the erythrocytic life cycle of the parasite showed that its action targets the synthesis of proteins by the parasite. With such a biological profile, girolline could be considered as a model chemical structure for new candidates in the arsenal of new drugs and in particular of drugs able to fight malaria.

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Synthesis of 5-deazathiogirollines: analogs of a natural antitumor agent

Cited by 22 publications

References 9 publications

Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

Enantioselective total synthesis of atpenin A5

Girolline: A Potential Lead Structure For Antiplasmodial Drug Research

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