Heterocyclic Analogues of Quinone Methide: Preparation and Cytotoxicity of 3-Oxo-3H-pyrazolo(1,5-a)indole Derivatives.

Katayama, Hajime; Tagawa, Naoyuki; Kawada, Yusuke; Shiobara, Keiichi; Kaneko, Kimiyoshi; Honda, Yurie; Kondo, Noriko; Ikeda, Yoshiaki

doi:10.1248/cpb.45.143

Cited by 5 publications

(4 citation statements)

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“…12), are also compounds that generate reactive alkylating QMs that mainly interact with DNA (they are structurally related to 25a, 25b, 27a, 27b, 28a, and 28b). These compounds, analogs of QMs, showed some cytotoxicity against some cancer cell lines, but were ineffective in an in vivo test against murine leukemia L1210 [94].…”

Section: Modulation Of Qm Reactivity Towards Nuc-leophiles Drugs Withmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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Section: Modulation Of Qm Reactivity Towards Nuc-leophiles Drugs Withmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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“…The residue was purified by column chromatography on silica gel using a mixture of EtOAc and hexanes (1:6) as the eluent to give 6a-e as liquids in 67-84% yields. [3,4]…”

Section: General Proceduresmentioning

confidence: 99%

“…Pyrazolo [1,5-a]indole, a condensed type of pyrazoloindole, has three possible isomers. The 4H-Pyrazolo [1,5-a]indole (1, Figure 1) is the most stable isomer as the 1H-isomer is isoelectronic to azulene [1,2], and the 3H-isomer is readily converted to 1 [3,4]. As a result, pyrazoloindole 1 and its derivatives are more frequently reported.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime

Huang,

Liao,

Hsu

et al. 2023

Molecules

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In this paper, we report the synthesis of spirocyclopropane-containing 4H-pyrazolo[1,5-a]indoles 6a–e via alkylative dearomatization and intramolecular N-imination of indole–O-(methylsulfonyl)oxime 11. Starting materials tryptophol (7) and 2-bromocyclopetanone (8) were reacted in the presence of HBF4·OEt2, providing 1,2,3,5,6,11-hexahydrocyclopenta[2,3]oxepino[4,5-b]indole (9) in a 63% yield. Compound 9 was reacted with hydroxylamine hydrochloride to afford oxime 10 (65% yield), which was subsequently bis-methanesulfonated to form 11 in a 85% yield. Heating 11 with various alcohols in the presence of N,N-diisopropylethylamine (DIPEA) triggered the alkylative dearomatization and intramolecular N-imination, forming the spirocyclopropane and 4H-pyrazolo[1,5-a]indole structures in the targets 6a–e with 67–84% yields.

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Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

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Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

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Heterocyclic Analogues of Quinone Methide: Preparation and Cytotoxicity of 3-Oxo-3H-pyrazolo(1,5-a)indole Derivatives.

Cited by 5 publications

References 0 publications

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Synthesis of Spirocyclopropane-Containing 4H-Pyrazolo[1,5-a]indoles via Alkylative Dearomatization and Intramolecular N-Imination of an Indole–O-(Methylsulfonyl)oxime

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

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