Tetrahydroisoquinolines – an updated patent review for cancer treatment (2016 – present)

ABSTRACT

Introduction

Cancer is a prominent cause of death globally, triggered by both non-genetic and genetic alterations in genes influenced by various environmental factors. The tetrahydroisoquinoline (THIQ), specifically 1,2,3,4-tetrahydroisoquinoline serves as fundamental element in various alkaloids, prevalent in proximity to quinoline and indole alkaloids.

Area covered

In this review, the therapeutic applications of THIQ derivatives as an anticancer agent from 2016 to 2024 have been examined. The patents were gathered through comprehensive searches of the Espacenet, Google patent, WIPO, and Sci Finder databases. The therapeutic areas encompassed in the patents include numerous targets of cancer.

Expert Opinion

THIQ analogues play a crucial role in medicinal chemistry, with many being integral to pharmacological processes and clinical trials. Numerous THIQ compounds have been synthesized for therapeutic purposes, notably in cancer treatment. They show great promise for developing anticancer drugs, demonstrating strong affinity and efficacy against various cancer targets. The creation of multi-target ligands is a compelling avenue for THIQ-based anticancer drug discovery.

KEYWORDS:

• Cancer
• anticancer agents
• cancer targets
• 1
• 2
• 3
• 4-tetrahydroisoquinoline
• PRMT5
• HPK1
• Bcl-xL

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Abbreviations

APs, apoptosis proteins; AML, acute myeloid leukemia; BIR, baculoviral IAP repeat domain; CAFs, cancer associated fibroblasts; CARD; caspase-recruitment domain; CDKs, cyclin-dependent kinases; DOPA, dihydroxyphenylalanine; DPP4, dipeptidyl peptidase 4; ER, oestrogen receptors; FAP, fibroblast activation protein-α; FGF, fibroblast growth factor; GDP, guanosine diphosphate; GLOBOCAN, global cancer observatory; GTP, guanosine triphosphate; HDI, human development index; HPK, hematopoietic progenitor kinase; IAP, inhibitor of apoptosis; KEAP, kelch-like ech-associated protein; NRF2, nuclear factor erythroid 2-related factor 2; PDE, phosphodiesterase; PDGF, platelet derived growth factor; PPAR, peroxisome proliferator-activated receptor; PROTAC, proteolysis targeting chimeric, PTPN; protein tyrosine phosphatase non-receptor; PRMTs, Protein Arginine Methyltransferases; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; SCID, Severe combined immunodeficiency; SERDs, Selective Estrogen Receptor Degraders; SERMs, Selective Estrogen Receptor Modulators; TGFβ, transforming growth factor-β; THIQ, tetrahydroisoquinoline; TNF, tumor necrosis factor; TR-FRET, time resolved-fluorescence resonance energy transfer; UBA, ubiquitin-associated domain; WNT, wingless type; WHO, world health organization.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

Ankur Kumar Tanwar - Literature search, literature collection, and initial writing

Neha Sengar - Literature search, literature collection, and initial writing

Nobuyuki Mase - Conceptualization, revieiwing, final drafting and editing of the manuscript.

Inder Pal Singh - Conceptualization, resource generation, reviewing, final drafting and editing of the manuscript

Acknowledgements

The authors are thankful to the Director, NIPER Mohali, for their support.

Article highlights

• This review covers the patent from 2016 to 2024 on THIQ derivatives as potential anti-cancer agents.

• THIQ scaffolds represent a significant family of heterocyclic molecules with potential use in drug discovery and therapeutic function diagnostics.

• Both synthesized and naturally occurring THIQs exhibit a wide range of biological activity, including notable cytotoxicity and potency in human cancer cell lines.

• With their ability to act through a variety of mechanisms, including inhibition of tubulin polymerization, cell proliferation, DNA fragmentation, induced cell cycle arrest, apoptosis, modulation, and disruption of cell migration, THIQ-based compounds demonstrate a significant role in the development of anticancer drugs or lead molecules.

• THIQs regulate various pathways of cancer by inhibiting or activating them, such as SERM, Wnt, PRMT5, Bcl2, Caspases, Nrf2/KEP1 HPK1 etc.

• In this review, numerous compounds of THIQ have been identified as effective anticancer molecules.

Additional information

Funding

This paper was not funded.