Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

Abstract

Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids.

An Overview of Antibody Conjugated Polymeric Nanoparticles for Breast Cancer Therapy

“…Biotin is a potential tumor-targeting moiety because it is a water-soluble vitamin (vitamin H), it is essential for growth and cell signaling, and their receptors are overexpressed on a broad range of cancer cells [122][123][124]. As an example of this non-covalent approach, the biotin-decorated PEG-PCL NPs were co-loaded with doxorubicin and quercetin to overcome doxorubicin-resistant breast cancer.…”

Two New Taxane Diterpenoids From Taxus baccata

“…Fraction C (1.6 g) was separated by silica gel column chromatography with the CH 2 Cl 2 -MeOH solvent system (starting from 80:1 to 1:10, v/v) to afford subfractions (C1-C5). These subfractions were further purified by RP-18 silica gel column with MeOH-H 2 O-formic acid solvent system (5:100:0.1 to 95: 19-Acetoxy-7,9,10-deacetyl-baccatin VI (2). White amorphous powder; [α] 25 D : −12.00 (c = 0.075, CHCl 3 ).…”

Design, Synthesis, and Anticancer Activity of Natural Product Hybrids With Paclitaxel Side Chain Inducing Apoptosis in Human Colon Cancer Cells

“…Taxol (1) and its semisynthetic derivatives docetaxel (Taxotere, 2) and cabazitaxel (Jevana, 3) ( Figure 1) are the most widely used drugs in chemotherapy and anticancer. 1 Their mechanism of action is closely related to their ability to promote polymerization of tubulin into microtubules by binding microtubules and stabilizing the cell division cycle of the G2/M phase.…”

“…Taxol (1) and its semisynthetic derivatives docetaxel (Taxotere, 2) and cabazitaxel (Jevana, 3) ( Figure 1) are the most widely used drugs in chemotherapy and anticancer. 1 Their mechanism of action is closely related to their ability to promote polymerization of tubulin into microtubules by binding microtubules and stabilizing the cell division cycle of the G2/M phase. 2,3 Based on the important role of taxoids, structure-activity relationships (SARs) have been studied in order to determine the minimal structural requirements necessary for biological activity, and the results highlighted the indispensable role of the unique C-13 side chains.…”