Pseudo-Natural Products: Expanding chemical and biological space by surpassing natural constraints.

This review explores the recent advancements in the design and synthesis of pseudo-natural products (pseudo-NPs) by employing innovative principles and strategies, heralding a transformative era in chemistry and biology. Pseudo-NPs, produced through in silico fragmentation and the de novo recombination of natural product fragments, reveal compounds endowed with distinct biological activities. Their advantage lies in transcending natural product structures, fostering diverse possibilities. Research in this area over the past decade has yielded unconventional combinations of natural product fragments, leading to the identification of novel compounds possessing unique scaffolds and biological significance, thereby contributing to the discovery of new therapeutics. The pseudo-NPs exert potent biological effects through various signaling pathways. In chemical biology and medicinal chemistry, designing pseudo-NPs is an important strategy, harnessing molecular hybridization and bioinspired synthesis to generate diverse compounds with remarkable biological activities, underscoring their immense potential in drug discovery and development.

Recent advances in the targeting of human DNA ligase I as a potential new strategy for cancer treatment.

The emergence of drug resistance, coupled with the issue of low tumor selectivity and toxicity is a major pitfall in cancer chemotherapy. It has necessitated the urgent need for the discovery of less toxic and more potent new anti-cancer pharmaceuticals, which target the interactive mechanisms involved in division and metastasis of cancer cells. Human DNA ligase I (hligI) plays an important role in DNA replication by linking Okazaki fragments on the lagging strand of DNA, and also participates in DNA damage repair processes. Dysregulation of the functioning of such ligases can severely impact DNA replication and repair pathways events that are generally targeted in cancer treatment. Although, several human DNA ligase inhibitors have been reported in the literature but unfortunately not a single inhibitor is currently being used in cancer chemotherapy. Results of pre-clinical studies also support the fact that human DNA ligases are an attractive target for the development of new anticancer agents which work by the selective inhibition of rapidly proliferating cancer cells. In this manuscript, we discuss, in brief, the structure, synthesis, structure-activity-relationship (SAR) and anticancer activity of recently reported hLigI inhibitors.