Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Abstract

Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

1,2-Diarylethanols—A New Class of Compounds That Are Toxic to E. coli K12, R2–R4 Strains

“…This compound was found to have antioxidant and anti-inflammatory properties [ 11 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Recently special attention was paid on combrestatin for its antimicrobial activity [ 11 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Due to its biological activity, combre...…”

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…The phosphates are intrinsically less active, particularly in terms of tubulin binding, as assessed in cell free assays [ 73 , 74 ], but non-specific phosphatases are abundant in cells providing rapid release of the active agents [ 75 ]. Recent reports have explored the encapsulation of combretastatin and DMXAA in targeted nanoparticles, sometimes in combination with co-encapsulated chemotherapy or anti-angiogenesis drugs to enhance tumor retention and prolong effective release [ 76 ]. While combretastatins have seen substantial progress in clinical development (Phase I–III clinical trials, Table 1 ), several other molecular structures can selectively lead to destruction of tumor vasculature and examples are shown in Figure 2 B.…”

Total synthesis of biselide A

“…Biselide A clustered with known compounds that can be categorized into two classes based on their impact on MT arrays. Class I compounds (which includes combretastatin A, 75 TH588, TH287 hydrochloride, 76 vinorelbine tartrate, 77 and epothilone B 78 ) directly bind to tubulin dimers in all MT arrays, including the spindle, within the cell. Class II compounds (which include INH6, 79 HMN-176, 80 dimethylenastron, 81 MK8745, 82 MLN905, 83 and NMS-P937 84 target non MT-components of the mitotic spindle.…”

“…Though these compounds have different targets, they result in similar cellular phenotypes due to their impact on MT arrays. Compounds in class I will impact MT dynamics in all MT arrays and cause MT spindle damage in a dose dependent manner, 75 whereas class II compounds largely affect MT array organization and MT dynamics within the spindle.…”