Journal of ISSN: 2473-0831 JAPLR

Analytical & Pharmaceutical Research
Mini Review
Volume 3 Issue 1 - 2016
The Combretastins A-1 and A-4 Prodrugs: A Mini-Review
John W Lippert III*
Department of Chemistry, Cyclics Corporation, USA
Received: July 23, 2016 | Published: September 07, 2016
*Corresponding author: John W Lippert III, Assistant Director of Chemistry, Cyclics Corporation, 7 University Place, Suite B212, Rensselaer, NY 12144, USA, Tel: 518-881-1408; Fax: 518-465-3121; E-mail:
Citation: Lippert JW (2016) The Combretastins A-1 and A-4 Prodrugs: A Mini-Review. J Anal Pharm Res 3(1): 00047. DOI: 10.15406/japlr.2016.03.00047


Both marine and terrestrial sources of natural products have afforded an impressive array of medicinally valuable compounds. The isolation and synthetic endeavors within the CRI at ASU has generated several candidates which are now in clinical development. Specifically, the compounds developed from the Eastern Cape South African Bushwillow tree, Combretum Caffrum, have always peaked a keen interest to the author.

Keywords: Synthetic derivatives; Combretastatin; Prodrug; Clinical trials; Stilbene


CRI: Cancer Research Institute; ASU: Arizona State University; CA1P: Combretastatin A-1 Prodrug; CA4P: Combretastatin A-4 Prodrug


The Cancer Research Institute at Arizona State University has isolated several marine and terrestrial natural products which have anti-cancer activity [1-5]. Tropical and subtropical shrubs and trees of the Combretaceae family represent a practically unexplored reservoir of new substances with potentially useful biological properties [6]. Illustrative of this is the genus Combretum (250 species), of which a number of their chemical constituents have found application in primitive medical treatment, although their structures have rarely been reported [6,7]. Primitive and tribal medical practices in India and Africa using the Combretum genus have found a broad range of use that include’s the treatment of leprosy (Combretum sp. roots) [6,8], cancer (Combretum latifolium) [6,9], mental illness (Combretum micranthum) [6,10,11], and scorpion invenomation (Combretum zeyheri) [6,12]. Other species within the Combretaceae genus that have received scientific investigation include Combretum molle (phenanthrenes) [7,13], Combretum elaeagnoides (triterpenoids) [7,14], Combretum quadrangulare (cycloartane-type triterpenes) [15] and the heartwood extracts from Combretum psidioides, Combretum hereroense, and Combretum apiculatum (9,10-dihydrophenanthrenes and phenanthrenes) [7,16] Still other chemical examinations [17] of this genus have included the isolation of cycloartane glycosides [18] and tannins [19]. Specifically, the compounds isolated from the Eastern Cape South African Bushwillow tree, Combretum Caffrum, are of main interest. These natural products designated the combretastins were isolated in the 1980s and are shown in Figure 1 [6-7,20-23]. By far, the most active constituents are those from the A-series having a cis-stilbene moiety.


To date the most interesting synthetic derivatives that are currently undergoing clinical development at Mateon Therapeutics (located in South San Francisco) are the combretastatin A-4 and combretastatin A-1 prodrugs [24-26]. Development of combretastatin A-4 (1d) to Phase I human cancer clinical trials was accelerated following synthesis of the phosphate prodrug 8 [27] and uncovering its very promising cancer antiangiogenesis effects [25,28-30]. The formation of water-soluble ester prodrugs has long been recognized as an effective means of increasing the aqueous solubility of drugs containing a hydroxyl group, with the aim of development of improved preparations for parenteral [31] or ophthalmic [32] administration [33]. Once administered, the phosphate prodrug is presumed to be converted into the parent drug via endogenous non-specific phosphatases and then transported intracellularly [25,27]. Phosphate 8 exhibited cytotoxicity similar to that of the parent compound (GI50 0.0004µg/mL, P388 cell line), but its aqueous solubility was much greater (20mg/mL) [34]. Prodrug 8 was also shown to induce vascular shutdown within murine metastatic tumors at doses less than one-tenth of the maximum tolerated dose [29]. A phosphate-type prodrug has also been shown to be a valuable synthetic modification for other anticancer drugs such as pancratistatin [35], taxol [36,37], tyrosine-containing peptides [38], and etoposide [39] owing to its ability to amplify drug solubility for enhanced delivery.

The preclinical development of combretastatin A-1 (1a) has been hampered owing to the instability (oxidation to the 1,2-quinone) of the 2,3-dihydroxy unit [40,41]. This was supported by the fact that acetylation of 1a significantly enhanced cytotoxicity 10-fold, while reducing inhibition of the tubulin assembly [40]. Interestingly, biosynthetic processes in Combretum kraussii have circumvented this problem by elaborating cis-stilbene 1a with a β-D-glucopyranosyl group at the 2-position of the B-ring [42] although biological evaluation has revealed it to be less active than the parent diphenol [43].

In spite of this superficially negative aspect, some biological properties exhibited by diphenol 1a (combretastatin A-1) make it attractive. For example, diphenol 1a may be the most potent antagonist of colchicine binding known, with nearly 99% inhibition at equal concentrations [40]. In addition, diphenol 1a was found to be more potent than monophenol 1d in its ability to increase intracellular daunorubicin (an antibiotic used in the treatment of acute leukemia) concentrations in MDR (multidrug resistant) cell lines [44]. Most importantly, the tubulin-binding stilbenes 1a (A-1) and 1d (A-4) elicit irreversible vascular shutdown selectively within solid tumors [45]. The degree of reduction ranged from 50% with diphenol 1a (A-1) to 70% with monophenol 1d (A-4) [45]. When a tumor reaches a critical mass (2-3mm), it becomes starved of oxygen and its cells begin secreting a messenger molecule, vascular endothelial growth factor (VEGF), to stimulate endothelial cells lining nearby blood vessels to form new capillaries (angiogenesis) for supplying oxygen [45]. Angiogenesis, the development and recruitment of new blood vessels, is a necessity for all tumor growth, and cancer specific antiangiogenic drugs such as combretastatin A-1 (1a) and A-4 (1d) are essential components for the inhibition of the metastatic pathway and are an attractive way to approach the cancer problem [46,47]. Recent biological experiments have noted that the combination of conventional chemotherapeutic agents with antiangiogenic agents has given significantly better results in reducing tumor metastases than was found with either agent alone [46] Other natural products such as taxol, tamoxifen, and adriamycin, which are already in clinical use as antitumor agents, are also being found to have antiangiogenic activity, increasing their overall therapeutic value [25,45,48].

Figure 1: The combretastatins.

Designated fosbretabulin (8) and Oxi4503 (9), respectively, these two synthetic derivatives are being used in various anti-cancer therapies [49]. Figure 2 illustrates the both the combretastatin A-4 and combretastatin A-1 prodrugs.

Figure 2: The CA1P and CA4P.


Both the CA4P (8) and CA1P (9) are important synthetic derivatives from the natural products known as the combretastatins. Each compound has advanced into the clinic for the treatment of specific classes of tumors [49].


The author would like to acknowledge all the research, both isolation and synthetic, that has gone on in the past at the CRI at ASU.


  1. Pettit GR, Tan R, Pettit RK, Doubek DL, Chapuis JC, et al. (2015) Antineoplastic agents 596. Isolation and structure of chromomycin A5 from a Beaufort Sea microorganism. RSC Advances 5(12): 9116-9122.
  2. Pettit GR, Smith TH, Arce PM, Flahive EJ, Anderson CR, et al. (2015) Antineoplastic Agents 599. Total Synthesis of Dolastatin 16. J Nat Prod 78(3): 476-485.
  3. Pettit GR, Arce PM, Chapuis JC, Macdonald CB (2015) Antineoplastic agents 600. From the South Pacific Ocean to the silstatins. J Nat Prod 78(3): 510-523.
  4. Kedei N, Kraft MB, Keck GE, Herald CL, Melody N, et al. (2015) Neristatin 1 Provides Critical Insight into Bryostatin 1 Structure-Function Relationships. J Nat Prod 78(4): 896-900.
  5. Pettit GR, Moser BR, Herald DL, Knight JC, Chapuis JC, et al. (2015) The Cephalostatins. 23. Conversion of Hecogenin to a Steroidal 1,6-Dioxaspiro[5.5] nonane Analogue for Cephalostatin 1. J Nat Prod 78(5): 1067-1072.
  6. Pettit GR, Singh SB, Niven ML, Hamel E, Schmidt JM (1987) Isolation, Structure, and Synthesis of Combretastatins A-1 and B-1, Potent New Inhibitors of Microtubule Assembly, Derived from Combretum caffrum. J Nat Prod 50(1): 119-131.
  7. Pettit GR, Singh SB, Schmidt JM, Niven ML, Hamel E, et al. (1988) Isolation, Structure, Synthesis, and Antimitotic Properties of Combretastatins B-3 and B-4 from Combretum caffrum. J Nat Prod 51(3): 517-527.
  8. Watt JM, Brandwijk BMG (1962) In Medicinal and Poisonous Plants of Southern and Eastern Africa. (2nd edn), E & S Livingstone, London, UK, pp. 1457.
  9. Private communication from Drs. Duke JA, Win JK, USDA, Beltsville, Maryland to Dr. Pettit GR.
  10. Ogan AU (1972) The Alkaloids In The Leaves Of Combretum Micranthum. Planta Med 21(2): 210-217.
  11. Malcolm SA, Sofowora EA (1969) Antimicrobial activity of selected Niegerian folk remedies and their constituent plants. Lloydia 32(4): 512-517.
  12. Mwauluka K, Charlwood BV, Briggs JM, Bell EA (1975) Biochem Physiol Pflanzen 168: 15.
  13. Letcher RM, Nhamo LRM, Gumiro IT (1972) Chemical constituents of the Combretaceae. Part II. Substituted phenanthrenes and 9,10-dihydrophenanthrenes and a substituted bibenzyl from the heartwood of Combretum molle. Journal of the Chemical Society, Perkin Transactions pp. 206.
  14. Osborne R, Pegel KH (1984) Jessic acid and related acid triterpenoids from combretum elaeagnoides. Phytochemistry 23(3): 635-637.
  15. Banskota AH, Tezuka Y, Phung LK, Tran KQ, Saiki I, et al. (1998) Cytotoxic cycloartane-type triterpenes from Combretum quadrangulare. Bioorg Med Chem Lett 8(24): 3519-3524.
  16. Letcher RM, Nhamo LRM. (1971) Chemical constituents of the combretaceae. Part I. Substituted phenanthrenes and 9,10-dihydrophenanthrenes from the heartwood of Combretum apiculatum. Journal of the Chemical Society pp. 3070-3076.
  17. Samuelsson G, Farah MH, Claeson P, Hagos M, Thulin M, et al. (1992) Inventory of plants used in traditional medicine in Somalia. II. Plants of the families Combretaceae to Labiatae. Journal of Ethnopharmacology 37(1): 47-70.
  18. Pegel KA, Rogers CB (1985) The characterisation of mollic acid 3β-D-xyloside and its genuine aglycone mollic acid, two novel 1α-hydroxycycloartenoids from combretum molle. Journal of the Chemical Society, Perkin Transactions I pp. 1711-1715.
  19. Wall ME, Taylor H, Ambrosio L, Davis K (1969) Plant antitumor agents III: A convenient separation of tannins from other plant constituents. J Pharm Sci 58(7): 839-841.
  20. Singh SB, Pettit GR (1989) Antineoplastic agents. 166. Isolation, structure, and synthesis of combretastatin C-1. JOC 54(17): 4105-4114.
  21. Pettit GR, Singh SB, Niven ML (1988) Antineoplastic agents. 160. Isolation and structure of combretastatin D-1: a cell growth inhibitory macrocyclic lactone from Combretum caffrum. JACS 110(25): 8539-8540.  
  22. Singh SB, Pettit GR (1990) Antineoplastic agents. 206. Structure of the cytostatic macrocyclic lactone combretastatin D-2. JOC 55(9): 2797-2800.
  23. Pettit GR, Singh SB, Niven ML, Schmidt JM (1988) Cell growth inhibitory dihydrophenanthrene and phenanthrene constituents of the african tree Combretumcaffrum. Canadian Journal of Chemistry 66(3): 406-413.
  24. Pettit GR, Temple CJR, Narayanan VL, Varma R, Simpson MJ, et al. (1995) Antineoplastic agents 322. synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des 10(4): 299-309.
  25. Pettit GR, Rhodes MR (1998) Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug. Anticancer Drug Des 13(3): 183-191.
  26. Pettit GR, Lippert JW III (2000) Antineoplastic Agents 429. Synthesis of the Combretastatin A-1 and B-1 Prodrug. Anticancer Drug Des 15(3): 203-216.
  27. Sloan KB (1992) Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. Prodrugs Topical and Ocular Drug Delivery. New York, USA, pp 17.
  28. Steiner, Weiss, Langer (1992) In Angiogenesis: Key Principles-Science-Technology-Medicine. Birkhauser, Basel, Swizerland 2: 449-454.
  29. Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR, et al. (1997) Combretastatin A-4, an Agent That Displays Potent and Selective Toxicity toward Tumor Vasculature. Cancer Res 57(10): 1829-1834.
  30. Takahashi H, Abe M, Sugawara, T, Tanaka K, Saito Y, et al. (1998) Clotrimazole, an Imidazole Antimycotic, Is a Potent Inhibitor of Angiogenesis. Jpn J Cancer Res 89(4): 445-451.
  31. Hensyl WR, Felscher H (1990) Parenteral-introduction of substances into an organism by intravenous, intramuscular, or intramedullary injection. (25th edn), Williams and Wilkins, Baltimore, USA, pp. 1139.
  32. Hensyl WR, Felscher H (1990) Ophthalmic-relating to the eye. (25th edn), Williams and Wilkins, Baltimore, USA, pp. 1093.
  33. Lee VH, Bundgaard H (1992) Improved Ocular Drug Delivery with Prodrugs. In: Sloan KB (Eds.), Marcel Dekker, New York, USA, pp. 237.
  34. Pettit GR, Rhodes MR, Herald DL, Chaplin DJ, Stratford M, et al. (1998) Antineoplastic agents 393. Synthesis of the trans-isomer of combretastatin A-4 prodrug. Anticancer Drug Des 13(8): 981-993.
  35. Pettit GR, Freeman S, Simpson MJ, Thompson MA. (1995) Antineoplastic agents 320: synthesis of a practical pancratistatin pro-drug. Anticancer Drug Des 10(3): 243-250.
  36. Ueda Y, Mikkilineni AB, Knipe JO, Rose WC, Casazza AM, et al. (1993) Novel water soluble phosphate prodrugs of taxol® possessing in vivo antitumor activity. Bioorganic & Medicinal Chemistry Letters 3(8): 1761-1766.
  37. Vyas DM, Wong H, Crosswell AR, Casazza AM, Knipe JO, et al. (1993) Synthesis and antitumor evaluation of water soluble taxol phosphates. Bioorganic & Medicinal Chemistry Letters 3(6): 1357-1360.
  38. Chao HG, Bernatowicz MS, Klimas CE, Matsueda GR (1993) N,N-Diisopropyl-bis[2-(trimethylsilyl)ethyl]phosphoramidite. An attractive phosphitylating agent compatible with the Fmoc/t-butyl strategy for the synthesis of phosphotyrosine containing peptides. Tetrahedron Letters 34(21): 3377-3380.
  39. Saulnier MG, Langley DR, Kadow JF, Senter PD, Knipe JO, et al. (1994) Synthesis of etoposide phosphate, BMY-40481: A water-soluble clinically active prodrug of etoposide. Bioorganic & Medicinal Chemistry Letters 4(21): 2567-2572.
  40. Lin CM, Singh SB, Chu PS, Dempcy RO, Schmidt JM, et al. (1988) Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. Mol Pharmacol 34(2): 200-208.
  41. Haines AH (1988) Methods for Oxidation of Organic Compounds. Academic Press: New York, USA, 2: pp 305-323.
  42. Pelizzoni F, Verotta L, Rogers CB, Colombo R, Pedrotti B, et al. (1993) Cell Growth Inhibitor Constituents From Combretum Kraussii. Natural Product Letters 1(4): 273-280.
  43. Orsini F, Pelizzoni F, Bellini B, Miglierini G (1997) Synthesis of biologically active polyphenolic glycosides (combretastatin and resveratrol series). Carbohydr Res 301(3-4): 95-109.
  44. McGown AT, Fox BW (1990) Differential cytotoxicity of Combretastatins A1 and A4 in two daunorubicin-resistant P388 cell lines. Cancer Chemother Pharmacol 26(1): 79-81.
  45. Lippert JW III (2007) Vascular Disrupting Agents. Bioorganic & Medicinal Chemistry 15(2): 605-615.
  46. Zetter BR (1998) Angiogenesis and Tumor Metastasis. Annu Rev Med 49: 407-424.
  47. Augustin HG (1998) Antiangiogenic tumour therapy: will it work? Trends Pharmacol Sci 19(6): 216-222.
  48. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, et al. (1996) The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2(11): 1843-1849.
© 2014-2018 MedCrave Group, All rights reserved. No part of this content may be reproduced or transmitted in any form or by any means as per the standard guidelines of fair use.
Creative Commons License Open Access by MedCrave Group is licensed under a Creative Commons Attribution 4.0 International License.
Based on a work at
Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version | Opera |Privacy Policy