Combretastatins: In vitro structure-activity relationship, mode of action and current clinical status.
For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency. The cis-configuration is crucial for its biological activity. To date, many derivatives were synthesized. The attempts to resolve spontaneous isomerization to less active trans-stilbene derivative are still in progress. This issue seems to be overcome by incorporation of the ethene bridge with heterocyclic moiety in combretastatins structure. This modification retains the cis-configuration and prevents isomerization. Nevertheless, combretastatin A4 phosphate disodium is still the most potent compound of this group. The combination therapy, which is the most effective treatment, includes combretastatin A4 phosphate (CA4P) and conventional chemotherapeutics and/or radiotherapy. CA4P is relatively well tolerated giving adverse events of moderate severity, which includes: nausea, vomiting, headache, and tumor pain. The aforementioned effects subside on the day of drug administration or on the following day.
Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland. Electronic address: karol.jaroch@cm.umk.pl.
Karol
K
Jaroch
Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Maciej
M
Karolak
Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Przemysław
P
Górski
Department and Institute of Nutrition and Dietetics, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland; Department and Clinic of Geriatrics, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Alina
A
Jaroch
Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Adrian
A
Krajewski
Faculty of Biotechnology, University of Wroclaw, Wrocław, Poland.
Aleksandra
A
Ilnicka
Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Anna
A
Sloderbach
Department of Chemical Technology of Drugs, Faculty of Pharmacy, Poznan University of Medical Sciences, Poznań, Poland; Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland.
Tomasz
T
Stefański
Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Stanisław
S
Sobiak
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D013267:Stilbenes / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; C058728:fosbretabulin
CA4P; Clinical trials; Combretastatin; SAR; Structure-activity relationship