Rational Design of Pyrrolo[1,2-a]benzimidazole-Based Antitumor Agents Targeting the DNA Major Groove

Huang, Xiaofen; Suleman, Ali; Skibo, Edward B.

doi:10.1006/bioo.2000.1183

Cited by 15 publications

(20 citation statements)

References 24 publications

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“…These models show that the His-194 residue in human model is closer to the other active site residues than the rat model and therefore better able to undergo hydrogen bonding interactions with substrates. 24 Since the positions of the important active site residues (other than His 194) are similar for both enzymes, superimposition of the duroquinone substrate complex of rat enzyme into the human active site is feasible.…”

Section: Resultsmentioning

confidence: 99%

A Comprehensive Study of the Active Site Residues of DT-Diaphorase: Rational Design of Benzimidazolediones as DT-Diaphorase Substrates

Suleman

Skibo

2002

J. Med. Chem.

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A series of quinone substrates were modeled into the active site of human DT-diaphorase and minimized. Correlation of these models with the substrate specificity k(cat)/K(m) provided insights into the structural requirements of quinone substrates. The W105, F106, and H194 residues can influence the position of the quinone substrate in the active site resulting in formation of one of the two possible Michael anions resulting from hydride transfer from FADH(2). Electron withdrawing groups on the substrate can stabilize these anions resulting in excellent substrate specificity. Inspection of models indicated that the W-105 and F-106 residues form parallel walls that will accommodate large polycyclic substrates. Thus excellent polycyclic substrates of DT-diaphorase were designed. However, the placement of tetrahedral centers on these polycyclic substrates interfered with the W-105 and the F-106 residues resulting in their exclusion from the active site. The histidine (H194) residue permits recognition of substrate enantiomers as a result of hydrogen bonding interactions. As a result of this study, it will be possible to design poor to excellent substrates of DT-diaphorase and take advantage of varying levels of this enzyme in histologically different cancers.

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Section: Resultsmentioning

confidence: 99%

A Comprehensive Study of the Active Site Residues of DT-Diaphorase: Rational Design of Benzimidazolediones as DT-Diaphorase Substrates

Suleman

Skibo

2002

J. Med. Chem.

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“…It is known that benzimidazoles exhibit a broad spectrum of biological activity of both human and veterinary importance (antiparasitic, antiviral, antimicrobial, fungicidal, herbicidal and insecticidal activity). A wide variety of benzimidazole derivatives have been described for their chemotherapeutic effects (Boruah & Skibo, 1994;Huang et al, 2000;El-masry et al, 2000). Owing to the presence of benzimidazole systems in a large number of common therapeutic agents (e.g.…”

Section: Commentmentioning

confidence: 99%

2-(1H-Benzimidazol-2-ylsulfanyl)butanoic acid

Langer¹,

Míčová²,

Steiner³

et al. 2006

Acta Cryst E

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The title compound, C11H12N2O2S, forms ionic crystals consisting of protonated benzimidazole cations and carboxylic acid anions, C11H13N2O2+·C11H11N2O2−. In both ions, the bicyclic 1H‐benzimidazole core is essentially planar. The plane of the 2‐alkylsulfanyl substituent is almost coplanar with the benzimidazole plane. The three‐dimensional packing is stabilized by strong intermolecular N—H⋯O and O—H⋯N interactions and weak C—H⋯O intermolecular hydrogen bonds.

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“…Skibo et al described a large number of 6-aziridinylpyrrolo[1,2-a]benzimidazole quinones (PBIs) [36][37][38][39]. Some of them, 10-14, are reported in (Fig.…”

Section: Pyrrolobenzimidazole Quinonesmentioning

confidence: 99%

Nitrogen-Containing Heterocyclic Quinones: A Class of Potential Selective Antitumor Agents

Garuti¹,

Roberti²,

Pizzirani³

2007

MRMC

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The development of prodrugs that are enzymatically activated into anticancer agents is a promising perspective in cancer therapy. Many nitrogen-containing quinoid heterocycles have been reported to show antitumor effect. The principal interest in these compounds lies on their potential to produce tumor-selective toxicity. Selectivity occurs by difference in oxygen tension between normal and tumor tissue and by levels of the required activating enzymes. In this review a summary of the most interesting heterocyclic quinones is given together with their biological property. SAR studies concerning the importance of some structural features will be described.

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Rational Design of Pyrrolo[1,2-a]benzimidazole-Based Antitumor Agents Targeting the DNA Major Groove

Cited by 15 publications

References 24 publications

A Comprehensive Study of the Active Site Residues of DT-Diaphorase: Rational Design of Benzimidazolediones as DT-Diaphorase Substrates

A Comprehensive Study of the Active Site Residues of DT-Diaphorase: Rational Design of Benzimidazolediones as DT-Diaphorase Substrates

2-(1H-Benzimidazol-2-ylsulfanyl)butanoic acid

Nitrogen-Containing Heterocyclic Quinones: A Class of Potential Selective Antitumor Agents

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