A facile and efficient method to synthesize pyrrole–imidazole was developed via a post-Ugi cascade reaction followed by one purification procedure. Synthesized pyrrole–imidazole was collected by performing a mild reaction and a simple procedure, which could be applicable to a broad scope of functionalized anilines. The screening results demonstrated that compound 7e exhibited a high potency of anticancer activity in human pancreatic cancer cell lines PANC and ASPC-1. Our work shed light on the potential of post-Ugi cascade reaction in combinatorial and medicinal chemistry.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Grube A, Köck M (2007) Structural assignment of tetrabromostyloguanidine: does the relative configuration of the palau’amines need revision? Angew Chem Int Ed 46:2320–2324. https://doi.org/10.1002/anie.200604076
Lanman BA, Overman LE, Paulini R, White NS (2007) On the structure of palau’amine: evidence for the revised relative configuration from chemical synthesis. J Am Chem Soc 129:12896–12900. https://doi.org/10.1021/ja074939x
Iwata M, Kamijoh Y, Yamamoto E, Yamanaka M, Nagasawa K (2017) Total synthesis of pyrrole-imidazole alkaloid (+)-cylindradine B. Org Lett 19:420–423. https://doi.org/10.1021/acs.orglett.6b03722
Dal Ben D, Antonini I, Buccioni M, Lambertucci C, Marucci G, Thomas A, Volpini R, Cristalli G (2011) Neuropeptide S receptor: recent updates on nonpeptide antagonist discovery. ChemMedChem 6:1163–1171. https://doi.org/10.1002/cmdc.201100038
Voss ME, Carter PH, Tebben AJ, Scherle PA, Brown GD, Thompson LA, Xu M, Lo YC, Yang G, Liu R-Q, Strzemienski P, Gerry Everlof J, Trzaskos JM, Decicco CP (2003) Both 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones and 3-thioxo-2,3-dihydro-1H-imidazo[1,5-α]indol-1-ones are light-dependent tumor necrosis factor-α antagonists. Bioorg Med Chem Lett 13:533–538. https://doi.org/10.1016/S0960-894X(02)00941-1
Zhang Y, Zheng J, Cui S (2014) Rh(III)-catalyzed C–H activation/cyclization of indoles and pyrroles: divergent synthesis of heterocycles. J Org Chem 79:6490–6500. https://doi.org/10.1021/jo500902n
Yamawaki I, Matsushita Y, Asaka N, Ohmori K, Nomura N, Ogawa K (1993) Synthesis and aldose reductase inhibitory activity of acetic acid derivatives of pyrrolo[1,2-c]imidazole. Eur J Med Chem 28:481–498. https://doi.org/10.1016/0223-5234(93)90016-8
Van-Gelder JM, Klein JY, Basel Y, Reizelman A, Tchilibon S, Mouallem O (2006) Preparation of rhodanine derivatives and analogs thereof as rigidified compounds for modulating heparanase activity. WO2006072953 A2
Mishriky N, Asaad FM, Ibrahim YA, Girgis AS (1998) Synthetic approaches towards 1H-pyrrolo[1,2-c]imidazoles. Pharmazie 53:607–611. https://doi.org/10.1002/chin.199850147
Sharp PP, Banwell MG, Renner J, Lohmann K, Willis AC (2013) Consecutive gold(I)-catalyzed cyclization reactions of o-(Buta-1,3-diyn-1-yl-)-substituted N-Aryl ureas: a one-pot synthesis of pyrimido[1,6-α]indol-1(2H)-ones and related systems. Org Lett 15:2616–2619. https://doi.org/10.1021/ol4007986
Fu S, Yang H, Li G, Deng Y, Jiang H, Zeng W (2015) Copper(II)-catalyzed enantioselective intramolecular cyclization of N-alkenylureas. Org Lett 17:1018–1021. https://doi.org/10.1021/acs.orglett.5b00131
Katritzky AR, Singh SK, Bobrov S (2004) Novel synthesis of bicycles with fused pyrrole, indole, oxazole, and imidazole rings. J Org Chem 69:9313–9315. https://doi.org/10.1021/jo0485334
Wang T, Shi S, Pflästerer D, Rettenmeier E, Rudolph M, Rominger F, Hashmi ASK (2014) Synthesis of polycyclic indole skeletons by a gold(I)-catalyzed cascade reaction. Chem Eur J 20:292–296. https://doi.org/10.1002/chem.201303539
Kong W-J, Chen X, Wang M, Dai H-X, Yu J-Q (2018) Rapid syntheses of heteroaryl-substituted imidazo[1,5-α]indole and pyrrolo[1,2-c]imidazole via aerobic C2–H functionalizations. Org Lett 20:284–287. https://doi.org/10.1021/acs.orglett.7b03596
Rajesh M, Puri S, Kant R, Reddy MS (2017) Ag-catalyzed intramolecular sequential vicinal diamination of alkynes with isocyanates: synthesis of fused indole-cyclic urea derivatives. J Org Chem 82:5169–5177. https://doi.org/10.1021/acs.joc.7b00417
Lei J, Xu Z-G, Li S-Q, Xu J, Zhu J, Chen Z-Z (2016) Synthesis of isoindolin-1-one derivatives via multicomponent reactions of methyl 2-formylbenzoate and intramolecular amidation. Mol Divers 20:859–865. https://doi.org/10.1007/s11030-016-9679-6
Li Y, Meng J-P, Lei J, Chen Z-Z, Tang D-Y, Zhu J, Zhang J, Xu Z-G (2017) Efficient synthesis of fused oxazepino-isoquinoline scaffolds via an Ugi, Followed by an intramolecular cyclization. ACS Comb Sci 19:324–330. https://doi.org/10.1021/acscombsci.7b00002
Xu Z-G, Ding Y, Meng J-P, Tang D-Y, Li Y, Lei J, Xu C, Chen Z-Z (2018) Facile construction of hydantoin scaffolds via a post-Ugi cascade reaction. Synlett 29:2199–2202. https://doi.org/10.1055/s-0037-1610234
McNab H, Tyas RG (2007) A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones. J Org Chem 72:8760–8769. https://doi.org/10.1021/jo0712502
Savelli F, Biodo A, Vazzana I, Sparatore F (1987) Tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepine and –cyclopenta[e]pyrido[2,3-b][1,4]diazepine derivatives. J Heterocycl Chem 24:1709–1716. https://doi.org/10.1002/jhet.5570240641
The authors would like to thank the Sichuan Provincial Science and Technology (2017fz0084), the Sichuan Province medical association (s15074), Chongqing Research Program of Basic Research and Frontier Technology (cstc2016jcyjA0534 and cstc2018jcyjAX0219) and the Scientific Research Foundation of the Chongqing University of Arts and Sciences (R2013XY01, R2015BX03, 2017ZBX05 and 2017ZBX10). We would also like to thank Ms H.Z. Liu for obtaining the LC/MS and NMR data.
Conflict of interest
The authors have declared no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Zhang, M., Ding, Y., Qin, HX. et al. One-pot synthesis of substituted pyrrole–imidazole derivatives with anticancer activity. Mol Divers 24, 1177–1184 (2020). https://doi.org/10.1007/s11030-019-09982-z
- Microwave irradiation
- One pot
- Anticancer activity