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Review
. 2024 Jan 5;14(3):1710-1728.
doi: 10.1039/d3ra07047f. eCollection 2024 Jan 3.

Pyrrolo[2,1- a]isoquinoline scaffolds for developing anti-cancer agents

Leidy J García Maza  1 , Arturo Mendoza Salgado  1 , Vladimir V Kouznetsov  2 , Carlos M Meléndez  1
Affiliations
Review

Pyrrolo[2,1- a]isoquinoline scaffolds for developing anti-cancer agents

Leidy J García Maza et al. RSC Adv. .

Abstract

Fused pyrrolo[2,1-a]isoquinolines have emerged as compelling molecules with remarkably potent cytotoxic activity and topoisomerase inhibitors. This comprehensive review delves into the intricate world of this family of compounds, analyzing the natural marine lamellarins known for their diverse and complex chemical structures, exploring structure-activity relationships (SARs), and highlighting their remarkable versatility. The review emphasizes their fundamental role as topoisomerase inhibitors and cytotoxic agents, as well as some crucial aspects of the chemistry of pyrrolo[2,1-a]isoquinolines, exploring synthetic strategies in total synthesis and molecular diversification trends, highlighting their importance in the field of medicinal chemistry and beyond.

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Conflict of interest statement

The authors declare nonfinancial interests/personal relationships, which may be considered as potential competing interests.

Figures

Fig. 1
Fig. 1. Scaffolds of fused type I and non-fused type II lamellarins with potent cytotoxic activity. The compound numbers correspond to the order of appearance throughout the text.
Fig. 2
Fig. 2. Some lamellarin compounds as promising inhibitors. (1) Lamellarins with potent anti-topoisomerase activity; (2) some lamellarins as potent protein kinase inhibitors.
Scheme 1
Scheme 1. Synthesis of lamellarins D (1) and H (16).
Scheme 2
Scheme 2. Synthesis of 1-dearyllamellarin D (66).
Scheme 3
Scheme 3. Total synthesis of lamellarin R (67).
Scheme 4
Scheme 4. Total synthesis of lam-D (1), lam-H (16), and lam-D trimethyl ether (82), through various Ru(ii)-catalyzed C–H activations.
Scheme 5
Scheme 5. General presentation of synthetic approaches for lam-G trimethyl ether (83) and its derivatives 100a–100d. Route 1: synthesis of lam-G trimethyl ether (83) by von Miller–Plöchl-Type cyclocondensation based on two different synthetic routes; Route 2: synthesis of dihydro-lamellarin ƞ (100b) and lamellarin ƞ (100d) from an intermediate of lam-G trimethyl ether 100a.
Scheme 6
Scheme 6. Synthesis of lamellarin D (1). Reagents and conditions: (i) iso-PrOH, t-BuOK, PhMe, DMPU, 80 °C, 3 h, 82%; (ii) Pd(PPh3)2Cl2, AcOK, DMA, 150 °C, 22 h, 80%; (iii) BCl3, DCM, −78 °C to r.t., 3.5 h, 99%.
Scheme 7
Scheme 7. Classical strategies for the isoquinoline synthesis.
Scheme 8
Scheme 8. Emerging synthetic approach for isoquinoline synthesis.
Scheme 9
Scheme 9. Intramolecular cyclization reactions and C–C bond formation on isoquinoline synthesis.
Scheme 10
Scheme 10. Brønsted and Lewis acid-catalyzed/Michael addition on isoquinoline synthesis.
Fig. 3
Fig. 3. General synthetic pathways for constructing pyrrolo[2,1-a]isoquinolines.
Scheme 11
Scheme 11. Current strategies on pyrrolo[2,1-a]isoquinolines synthesis.
Scheme 12
Scheme 12. Synthesis of pyrrolo[2,1-a]isoquinoline pseudo-natural products.
Scheme 13
Scheme 13. Pyrrolo[2,1-a]isoquinoline analogs as anti-cancer agents, structure–activity relationship analysis.
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