Advances in anticancer alkaloid-derived metallo-chemotherapeutic agents in the last decade: Mechanism of action and future prospects

Metal-based complexes have occupied a pioneering niche in the treatment of many chronic diseases, including various types of cancers. Despite the phenomenal success of cisplatin for the treatment of many solid malignan-cies, a limited number of metallo-drugs are in clinical use against cancer chemotherapy till date. While many other prominent platinum and non-platinum-based metallo-drugs (e.g. NAMI-A, KP1019, carboplatin, oxali-platin, titanocene dichloride, casiopeinas (R) etc) have entered clinical trials, many have failed at later stages of R&D due to deleterious toxic effects, intrinsic resistance and poor pharmacokinetic response and low therapeutic efficacy. Nonetheless, research in the area of medicinal inorganic chemistry has been increasing exponentially over the years, employing novel target based drug design strategies aimed at improving pharmacological out-comes and at the same time mitigating the side-effects of these drug entities. Over the last few decades, natural products became one of the key structural motifs in the anticancer drug development. Many eminent researchers in the area of medicinal chemistry are devoted to develop new 3d-transition metal-based anticancer drugs/ repurpose the existing bioactive compounds derived from myriad pharmacophores such as coumarins, flavo-noids, chromones, alkaloids etc. Metal complexes of natural alkaloids and their analogs such as luotonin A, jatrorrhizine, berberine, oxoaporphine, 8-oxychinoline etc. have gained prominence in the anticancer drug devel-opment process as the naturally occurring alkaloids can be anti-proliferative, induce apoptosis and exhibit inhi-bition of angiogenesis with better healing effect. While some of them are inhibitors of ERK signal-regulated kinases, others show activity based on cyclooxygenases-2 (COX-2) and telomerase inhibition. However, the tar -gets of these alkaloid complexes are still unclear, though it is well-established that they demonstrate anticancer potency by interfering with multiple pathways of tumorigenesis and tumor progression both in vitro and in vivo. Over the last decade, many significant advances have been made towards the development of natural alkaloid -based metallo-drug therapeutics for intervention in cancer chemotherapy that have been summarized below and reviewed in this article.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Metal-based complexes have been at the forefront of treating chronic diseases, particularly different types of cancers. While cisplatin has been successful, few metallo-drugs are currently used in cancer chemotherapy due to toxic effects and limited efficacy. However, research in medicinal inorganic chemistry has been growing rapidly, focusing on novel drug design strategies to improve outcomes and reduce side effects. Natural products, such as alkaloids, have become key elements in anticancer drug development. Metal complexes of natural alkaloids have shown promise in inhibiting tumor progression through various pathways. Despite unclear targets, these complexes have exhibited anticancer potency both in vitro and in vivo. Advances have been made in the development of natural alkaloid-based metallo-drugs for cancer chemotherapy.