Day: December 6, 2020

Perspectives on Biologically Active Camptothecin Derivatives

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.


Camptothecin (CPT) is a pentacyclic alkaloid isolated by Wall et al. in the early 1960s from the Chinese tree Camptotheca acuminata. This compound attracted immediate interest as a potential cancer chemotherapeutic agent due to its impressive activity against leukemias and various solid tumors in experimental systems. Due to CPT’s negligible water solubility, clinical trials were initiated using the water-soluble sodium salt of CPT in the early 1970s. The trials were suspended in the 1970s due to lower efficacy of 2, accompanied by unpredictable and severe levels of toxicity, including hemorrhagic cystitis and myelotoxicity. Interest in CPT then subsided for over a decade. Revived attention resulted from the breakthrough discovery of DNA topoisomerase I (Topo I) as a therapeutic target for CPT. This discovery put CPT back on the frontlines of anticancer drug development in the late 1980s. Accordingly, CPT’s total synthesis, mechanism of action, structure–activity relationship (SAR), analog synthesis as well as pharmacology, formulation, drug delivery, preclinical studies and clinical trials have been studied extensively. Recent interesting research approaches include using prodrug concepts and drug delivery systems for CPT.
As the result of these renewed research efforts, three CPT analogues, topotecan (TPT), irinotecan (CPT-11), and belotecan (CKD-602), received governmental approval for the clinical treatment of ovarian, small-cell lung, and refractory colorectal cancers. Three additional water-soluble analogues, exatecan (DX-8951f) lurtotecan (GG-211), and sinotecan, are currently under clinical evaluation. (Med Res Rev. 2015 Jul; 35(4): 753–789.)

Polymer–drug conjugates: recent advances and future perspectives

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Polymer–drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such as a combination of polymers and polysaccharides, to explore dual benefits such as combined vehicles and targeting moieties. Polymer heterogeneity, synthesis of PDCs, broad molecular weight distribution, conjugate variability, immunogenicity of polymers, safety, stability, and stringent regulatory approval are the major obstacles to the successful transition of PDCs to the clinic. In this review, we discuss natural and synthetic PDCs combined with computational modeling for diverse pharmaceutical and biomedical applications. (Drug Discovery Today. Volume 25, Issue 9, September 2020, Pages 1718-1726.)