Cryptophycin

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The common core structure of cryptophycins colored by division into four fragments, two amino and two hydroxy acids.

Cryptophycins are a family of macrolide molecules that are potent cytotoxins and have been studied for potential antiproliferative properties useful in developing chemotherapy. They are members of the depsipeptide family.

History[edit]

Cryptophycins were originally discovered in 1990 in cyanobacteria of the genus Nostoc.[1] Cryptophycins were patented as antifungal agents with an unknown mechanism of action and subsequently identified as microtubule inhibitors.[2] Closely related molecules were reported in the marine sponge Dysidea arenaria, which were first given the name arenastatins.[3] However, since cyanobacteria are common symbionts of sponges, it has been suggested that bacteria may be the true origin in cases where sponge and bacterial metabolites closely resemble one another.[4] Nevertheless, study of the structure-activity relationships between the two subgroups of molecules led to improved understanding of their cytotoxic effects.[5]:230

Mechanism of action[edit]

Cryptophycins are potent microtubule inhibitors, with a mechanism of action similar to that of vinca alkaloids.[2][6][7] Treatment of cells with cryptophycins depletes microtubules through interaction with tubulin, thereby preventing cell division.[8] Cryptophycins are capable of inducing apoptosis,[9] possibly through other mechanisms in addition to that mediated by microtubule inhibition.[10]

Clinical studies[edit]

Members of the cryptophycin family have been studied as anti-tumor agents. Cryptophycin-52, a synthetic analog of natural product cryptophycins also known as LY355703,[11] reached phase II clinical trials but was withdrawn due to side effects.[12]

Synthesis[edit]

Cryptophycins were first isolated from cyanobacteria but have subsequently been produced by chemical synthesis.[13][14] Chemoenzymatic syntheses have also been reported.[15][16]

References[edit]

  1. ^ Schwartz, Robert E.; Hirsch, Charles F.; Sesin, David F.; Flor, James E.; Chartrain, Michel; Fromtling, Robert E.; Harris, Guy H.; Salvatore, Michael J.; Liesch, Jerrold M.; Yudin, Katherine (April 1990). "Pharmaceuticals from cultured algae". Journal of Industrial Microbiology. 5 (2–3): 113–123. doi:10.1007/BF01573860.
  2. ^ a b Smith, CD; Zhang, X; Mooberry, SL; Patterson, GM; Moore, RE (15 July 1994). "Cryptophycin: a new antimicrotubule agent active against drug-resistant cells". Cancer Research. 54 (14): 3779–84. PMID 7913408.
  3. ^ KOBAYASHI, Motomasa; KUROSU, Michio; OHYABU, Naoki; WANG, Weiqi; FUJII, Satoshi; KITAGAWA, Isao (1994). "The Absolute Stereostructure of Arenastatin A, a Potent Cytotoxic Depsipeptide from the Okinawan Marine Sponge Dysidea arenaria". Chemical & Pharmaceutical Bulletin. 42 (10): 2196–2198. doi:10.1248/cpb.42.2196.
  4. ^ Piel, Jörn (2004-01-01). "Metabolites from symbiotic bacteriaThis review is dedicated to Professor Axel Zeeck on the occasion of his 65th birthday". Natural Product Reports. 21 (4): 519–38. doi:10.1039/b310175b. PMID 15282634.
  5. ^ Cragg, edited by Gordon M.; Kingston,, David G.I.; Newman, David J. (2012). Anticancer agents from natural products (2nd ed.). Boca Raton, FL: CRC Press. ISBN 9781439813836.
  6. ^ Panda, D; DeLuca, K; Williams, D; Jordan, MA; Wilson, L (4 August 1998). "Antiproliferative mechanism of action of cryptophycin-52: kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends". Proceedings of the National Academy of Sciences of the United States of America. 95 (16): 9313–8. Bibcode:1998PNAS...95.9313P. doi:10.1073/pnas.95.16.9313. PMC 21335. PMID 9689077.
  7. ^ Panda, D; Himes, RH; Moore, RE; Wilson, L; Jordan, MA (21 October 1997). "Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1". Biochemistry. 36 (42): 12948–53. doi:10.1021/bi971302p. PMID 9335554.
  8. ^ Zhang, X. (15 March 1996). "Mechanism of Action of Cryptophycin". Journal of Biological Chemistry. 271 (11): 6192–6198. doi:10.1074/jbc.271.11.6192.
  9. ^ Mooberry, SL; Busquets, L; Tien, G (4 November 1997). "Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent". International Journal of Cancer. 73 (3): 440–8. doi:10.1002/(sici)1097-0215(19971104)73:3<440::aid-ijc20>3.3.co;2-x. PMID 9359493.
  10. ^ Drew, L; Fine, RL; Do, TN; Douglas, GP; Petrylak, DP (December 2002). "The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells". Clinical Cancer Research. 8 (12): 3922–32. PMID 12473608.
  11. ^ Trimurtulu, Golakoti; Ohtani, Ikuko; Patterson, Gregory M. L.; Moore, Richard E.; Corbett, Thomas H.; Valeriote, Frederick A.; Demchik, Lisa (June 1994). "Total Structures of Cryptophycins, Potent Antitumor Depsipeptides from the Blue-Green Alga Nostoc sp. Strain GSV 224". Journal of the American Chemical Society. 116 (11): 4729–4737. doi:10.1021/ja00090a020.
  12. ^ Field, Jessica J.; Kanakkanthara, Arun; Miller, John H. (September 2014). "Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function". Bioorganic & Medicinal Chemistry. 22 (18): 5050–5059. doi:10.1016/j.bmc.2014.02.035. PMID 24650703.
  13. ^ Bolduc, KL; Larsen, SD; Sherman, DH (22 May 2012). "Efficient, divergent synthesis of cryptophycin unit A analogues". Chemical communications (Cambridge, England). 48: 6414. doi:10.1039/c2cc32417b. PMC 3494784. PMID 22617820.
  14. ^ Weiß, C; Bogner, T; Sammet, B; Sewald, N (2012). "Total synthesis and biological evaluation of fluorinated cryptophycins". Beilstein journal of organic chemistry. 8: 2060–6. doi:10.3762/bjoc.8.231. PMC 3511040. PMID 23209540.
  15. ^ Magarvey, NA; Beck, ZQ; Golakoti, T; Ding, Y; Huber, U; Hemscheidt, TK; Abelson, D; Moore, RE; Sherman, DH (15 December 2006). "Biosynthetic characterization and chemoenzymatic assembly of the cryptophycins. Potent anticancer agents from cyanobionts". ACS Chemical Biology. 1 (12): 766–79. doi:10.1021/cb6004307. PMID 17240975.
  16. ^ Ding, Y; Rath, CM; Bolduc, KL; Håkansson, K; Sherman, DH (21 September 2011). "Chemoenzymatic synthesis of cryptophycin anticancer agents by an ester bond-forming non-ribosomal peptide synthetase module". Journal of the American Chemical Society. 133 (37): 14492–5. doi:10.1021/ja204716f. PMC 3174474. PMID 21823639.