A New Survey about Dual-Acting PARP/COX-2 Inhibitors as Cancer Chemopreventive Agents.

Abstract

Context: Poly(ADP-ribose) polymerase (PARP) is a key enzyme involved in DNA replication. Studies have shown that this enzyme plays a pivotal role in apoptosis and DNA damage repair. Excessive PARP activity, particularly that of PARP-1, may also lead to uncontrolled cellular growth and proliferation, thereby predisposing to tumor development. Similar effects have been observed with the overexpression of cyclooxygenase-2 (COX-2) in cancer development. In this review, our primary objective is to provide a concise and comprehensive structure-activity relationship to guide the design of compounds with dual inhibitory activity against PARP and COX-2. On the basis of this relationship, this review aims to support the development of novel compounds with potent inhibitory activity against PARP-1, as well as the design of dual PARP-1/COX-2 inhibitors.

Evidence acquisition: A comprehensive literature search was conducted to identify relevant studies on the design, synthesis, and biological evaluation of novel PARP and PARP-1 inhibitors, as well as dual-acting PARP-1/COX-2 inhibitors. Electronic databases, including Scopus, ScienceDirect, and Google Scholar, were systematically searched. Research articles published in English up to the most recent available date were considered. Studies were screened for relevance, clarity, and compliance with recognized molecular design guidelines. The collected information was analyzed and synthesized to provide an overview of the current state of PARP-1/COX-2 inhibitor synthesis approaches and design trends.

Results: Based on the review findings, the use of PARP-1/COX-2 dual inhibitors may be considered a viable therapeutic approach for targeting two interconnected pathways involved in cancer development. Dual-acting agents provide an opportunity to enhance anticancer efficacy and reduce resistance to malignancy. Moreover, preclinical studies have demonstrated synergistic effects. Notably, there are substantial similarities between the SAR of single- and dual-acting PARP-1/COX-2 inhibitors. In addition, polycyclic core structures could be used to guide the design of these compounds. Furthermore, these polycyclic structures may exhibit other important antineoplastic properties, such as inhibition of topoisomerase II (TPO-II).

Conclusions: In summary, to provide a more comprehensive review of the design and synthesis of novel chemical compounds as COX-2/PARP-1 dual inhibitors, additional compounds must be developed. Moreover, further clinical development and evaluation are required to improve their pharmacological properties and confirm their safety and efficacy in clinical settings.