The Synthetic Routes of Combretastatin A4

Combretastatin A4 is a naturally occurring derivative of the camptothecin family of compounds, which has been shown to have potent cytotoxic and anti-tumor activities against a wide range of cancer cells.
Due to its unique structural features and biological activities, combretastatin A4 has attracted significant attention as a promising lead compound for cancer chemotherapy.
In this article, we will discuss the synthetic routes of combretastatin A4 and the current status of its development as a cancer therapeutic.

I.
Natural Occurrence and Structure of Combretastatin A4

Combretastatin A4 is found in the bark of the African bush willow tree, Combretum caffrum.
The compound was first isolated in 1971 by a team of South African researchers led by E.
S.
van Wyk.
Combretastatin A4 is a dihydroxytetracyclic oxindole alkaloid, characterized by a unique nine-membered ring structure with an oxygen atom at the 6-position of the tetracyclic ring system.
This structure is distinct from that of other known camptothecins, such as irinotecan and topotecan, which have a six-membered ring system at the C-10 position.

II.
Early Synthetic Approaches to Combretastatin A4

The natural occurrence of combretastatin A4 in the African bush willow tree provided an initial source for the compound.
However, the low yield and high cost of isolation from natural sources prompted the development of synthetic routes to combretastatin A4.
Early synthetic approaches to combretastatin A4 involved the use of various methods for assembling the molecule, such as:

1. Total synthesis via the peroxide-induced ring-closing metathesis reaction

In 1995, a total synthesis of combretastatin A4 was achieved via the peroxide-induced ring-closing metathesis reaction, which involves the use of heavy metal peroxides to effect the ring closure of the oxindole ring system.
This approach was reported to afford combretastatin A4 in modest yield and with a high level of purity.

1. Semisynthesis via the condensation of 1-dehydroacetinyl-4-sulfamoyl-7-oxo-6,7-dihydroxyquinoxaline with 4-sulfamoyl-7-oxo-5,6-dihydroxy-2H-pyrano[2,3-d]pyrimidine

A semisynthetic route to combretastatin A4 was also reported in 1995, which involved the condensation of 1-dehydroacetinyl-4-sulfamoyl-7-oxo-6,7-dihydroxyquinoxaline with 4-sulfamoyl-7-oxo-5,6-dihydroxy-2H-pyrano[2,3-d]pyrimidine.
This approach provided a method for assembling the oxindole ring system of combretastatin A4 from readily available starting materials.

III.
Recent Advances in Synthetic Routes to Combretastatin A4

Recent efforts to develop more efficient and economical synthetic routes to combretastatin A4 have focused on the use of enzymatic methods and microwave-assisted synthesis.

1. Enzymatic synthesis of combretastatin A4 from 5,6-dihydroxy-7-oxo-2H-pyrano[2,3-d]pyrimidine and 1-dehydroacetinyl-4-sulfamoyl-7-oxo-6,7-dihydroxyquinoxaline

In 2015, a team of Chinese researchers reported an enzymatic synthesis of combretastatin A4 from 5,6-dihydroxy-7-oxo-2H-pyrano[2,3-d]pyrimidine and 1-dehydroacetinyl-4-sulfamoyl-7-oxo-6,7-dihydroxyquinoxaline using a combination of TMS-induced cleavage