The Organic Chemistry of the Pyrrolo[1,2-a]benzimidazole Antitumor Agents. An Example of Rational Drug Design

Skibo, Edward B.; Islam, Imadul; Schulz, William G.; Zhou, Ru; Bess, Laura S.; Boruah, Romesh C.

doi:10.1055/s-1996-5399

Cited by 43 publications

(49 citation statements)

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“…The occurrence of the pyrrolo [1,2-a]imidazole unit in several biologically active compounds, for example, several classes of pyrrolo [1,2-a]benzimidazole-based antitumor agents [29] increases the interest in this [6+2] cyclization reaction.…”

Section: Resultsmentioning

confidence: 99%

Facile and Versatile Annulation of the Imidazole Ring: Single and Sequential Cyclization Reactions of Fischer Carbene Complexes with 1,4‐Diazafulvenes

Barluenga¹,

García-Rodríguez²,

Martı́nez³

et al. 2006

Chemistry A European J

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We examined the reactivity of dimethylaminodiazafulvene 1 toward Fischer alkenylcarbene 2 and alkynylcarbene 3 complexes. Diazafulvene 1 reacts with alkenylcarbenes 2 through a formal [6+3] heterocyclization in a regio- and stereoselective manner to afford dihydroimidazo[1,2-a]pyridines 4. Acid-promoted dimethylamine elimination in compound 4 c gives rise to the aromatic imidazo pyridine 5. A likely mechanism for this reaction is a 1,2-nucleophilic addition/[1,2]-shift metal-promoted cyclization sequence. On the other hand, diazafulvene 1 and alkynyl carbenes 3 undergo a [6+2] cyclization to afford pyrrolo[1,2-a]imidazole carbene complex 6 that can be readily oxidized to the corresponding esters 7. When enynylcarbenes 3 e-i are treated with diazafulvene 1, consecutive and diastereoselective [6+2]/cyclopentannulation cyclization reactions take place affording new polycyclic complex systems 8, 9, and 12 that can be appropriately demetallated to the corresponding imidazole-based polyfused systems 10, 11, and 13 respectively. Finally, enynylcarbenes 3 d,f undergo consecutive [6+2]/[5+1] cyclization reactions with diazafulvene 1 and tBuNC, respectively, to yield tetracyclic adducts 14 and 15. All these processes result in high yields and provide a route to the preparation of imidazopyridines and pyrroloimidazoles as well as other polycyclic molecules that contain imidazole groups, which are interesting from a pharmacological and biological point of view.

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Section: Resultsmentioning

confidence: 99%

Facile and Versatile Annulation of the Imidazole Ring: Single and Sequential Cyclization Reactions of Fischer Carbene Complexes with 1,4‐Diazafulvenes

Barluenga¹,

García-Rodríguez²,

Martı́nez³

et al. 2006

Chemistry A European J

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“…[1][2][3][4] The 6-aziridinyl analogues were shown to be most cytotoxic against a variety of cancer cell lines (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…Evidence for reductive activation of PBI to the hydroquinone was reported to lead to an intermediate that hydrogen bonds to the DNA major groove at the AT base pair with nucleophilic alkylation at the aziridine by the phosphate backbone of DNA resulting in hydrolytic strand cleavage. 1,3 More recently, our group has introduced [1,2-a] alicyclic ring-fused benzimidazolequinones with (e.g., 1 and 2) and without an additional fused cyclopropane ring. [5][6][7] The cytotoxicity of these compounds towards human skin fibroblast cells was found to be in the nanomolar range (10 À9 M) with cytotoxicity increasing under the hypoxic conditions associated with solid tumours.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4]6,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] The procedures can be categorized into the following cyclization protocols: (i) metalcatalyzed reduction of aromatic nitro groups to amines (or nitroso), which undergo acid-catalyzed cyclization onto adjacent azacycloalkanes; [1][2][3][4]9,11,13,14 (ii) nucleophilic displacement by the N-1 benzimidazole anion of halo substituents in 2-(x-haloalkyl)benzimidazoles or generation of the benzimidazol-2-yl anion to undergo the inverse displacement reaction; 10,12,17,19 (iii) Rh-catalyzed reaction of N-alkenyl-1,2-diaminobenzene with H 2 and CO followed by annulation; 16 (v) N-nucleophilic anionic aromatic substitution using activated aromatic amidine analogues. 8,15,20 However, none of these synthetic approaches have thus far been reported to give eight-membered [1,2-a] alicyclic ring-fused benzimidazoles (e.g., 4).…”

Section: Introductionmentioning

confidence: 99%

“…The mechanism for this cyclization probably involves oxidation to the iminium ion followed by nucleophilic attack by the adjacent acetamido nitrogen. 1,2 Zhou and Skibo reported nitration at the 5-position (in 38% yield) when 6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole was treated with fuming nitric acid using a salt-ice water bath for 5 min. 2 In our hands this procedure gave an almost equal mixture of two nitro isomers 10 24 and 11 when using 3-methoxy- 6 only the 2,4-dinitrated product 12 is obtained.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of seven- and eight-membered [1,2-a] alicyclic ring-fused benzimidazoles and 3-aziridinylazepino[1,2-a]benzimidazolequinone as a potential antitumour agent

Fahey

Aldabbagh

2008

Tetrahedron Letters

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Synthesis by Radical Cyclization and Cytotoxicity of Highly Potent Bioreductive Alicyclic Ring Fused [1,2‐a]Benzimidazolequinones

Lynch

Hehir

Kavanagh

et al. 2007

Chemistry A European J

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The key step in the synthesis of new five, six and seven-membered alicyclic ring [1,2-a]-fused bioreductive benzimidazolequinones was radical cyclisation. Six and seven-membered tributyltin hydride-mediated homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred in high yields (63-70 %) when quaternising the pyridine-like 3-N of imidazole with camphorsulfonic acid and using large excesses of the azo-initiator, 1,1'-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. Elaboration of benzimidazoles to the benzimidazolequinones occurred in excellent yields. The IC50 values for the cytotoxicity of benzimidazolequinones towards the human skin fibroblast cell line GM00637 were in the nanomolar range, as determined by using the MTT assay. The benzimidazolequinones were much more cytotoxic than indolequinone analogues. 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole-6,9-dione was the most potent compound prepared being more than 300 times more cytotoxic than the clinically used bioreductive drug, mitomycin C. The latter benzimidazolequinone was more potent under hypoxic conditions (associated with solid tumors), being 4.4 times more cytotoxic than under aerobic conditions, while mitomycin C was 1.8 times more selective towards hypoxia. The cyclopropane fused pyrido[1,2-a]benzimidazolequinone, 1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrido[1,2-a]benzimidazole-5,8-dione was less cytotoxic and selective than the five-membered ring analogue, 1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benzimidazole-3,6-dione. Modifying the structure of the most potent pyrido[1,2-a]benzimidazolequinone by attaching methyl substituents onto the quinone moiety increased reductive potentials and decreased cytotoxicity and selectivity towards hypoxia.

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The Organic Chemistry of the Pyrrolo[1,2-a]benzimidazole Antitumor Agents. An Example of Rational Drug Design

Cited by 43 publications

References 0 publications

Facile and Versatile Annulation of the Imidazole Ring: Single and Sequential Cyclization Reactions of Fischer Carbene Complexes with 1,4‐Diazafulvenes

Facile and Versatile Annulation of the Imidazole Ring: Single and Sequential Cyclization Reactions of Fischer Carbene Complexes with 1,4‐Diazafulvenes

Synthesis of seven- and eight-membered [1,2-a] alicyclic ring-fused benzimidazoles and 3-aziridinylazepino[1,2-a]benzimidazolequinone as a potential antitumour agent

Synthesis by Radical Cyclization and Cytotoxicity of Highly Potent Bioreductive Alicyclic Ring Fused [1,2‐a]Benzimidazolequinones

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