1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design

ABSTRACT

Introduction: Cancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design.

Areas covered: This review article addresses the potential of THIQ as anticancer agents. Various medicinal chemistry strategies employed for the design and development of THIQ analogs as inhibitors or modulators of relevant anticancer targets have been discussed in detail. Moreover, the common strategies employed for the synthesis of the core scaffold are also highlighted.

Expert opinion: Evidently, THIQs have tremendous potential in anticancer drug design. Some of these analogs exhibited potent activity against various cancer molecular targets. However, there are some drawbacks, such as selectivity that need addressing. The synthetic ease for constructing the core scaffold complimented with its reactivity makes it ideal for further structure-activity relationship studies. For these reasons, THIQ is a privileged scaffold for the design and development of novel anticancer agents.

KEYWORDS:

• Tumor
• epigenetics
• apoptotic proteins
• resistance
• synthesis
• 1, 2, 3, 4-tetrahydro-2-azanaphthalene
• 3, 4-dihydro-1H-isoquinoline
• benzo piperidine

Article highlights

• The complex milieu of tumor cells accompanied by the drawbacks of existing drugs warrants the development of new drugs to treat cancers.

• THIQ is a widely explored heterocyclic scaffold that has been demonstrated to possess various pharmacological activities. It is also present in several clinically used drug molecules.

• Various studies have unearthed the promising prospects of THIQ as anticancer agents.

• THIQ exhibits its anticancer activity by inhibiting several epigenetic enzymes, anti-apoptotic proteins, transporters, and receptors.

• However, some aspects of THIQ analogs, such as selectivity, need addressing. The selectivity of THIQ analogs can be improved by detailed structure-activity relationship studies and molecular modeling studies.

This box summarizes key points contained in the article.

Declaration of interest

The author(s) acknowledge the support of BITS-Pilani, the Pilani campus for providing facilities to do this research. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

Faheem, BK Kumar, S Murugesan and KV Gowri Chandra Sekhar gratefully acknowledge funding from the Department of Biotechnology Indo-Spain, New Delhi. (Ref. No: BT/IN/Spain/39/SM/2017-2018). Additionally, B Karan Kumar is thankful to the Ministry of Tribal affairs, Government of India for providing financial assistance (Award no- 201920-NFST-TEL-01497).