:Cryptophycin

Cryptophycins were originally discovered in 1990 in cyanobacteria of the genus Nostoc.{{cite journal|last1=Schwartz|first1=Robert E.|last2=Hirsch|first2=Charles F.|last3=Sesin|first3=David F.|last4=Flor|first4=James E.|last5=Chartrain|first5=Michel|last6=Fromtling|first6=Robert E.|last7=Harris|first7=Guy H.|last8=Salvatore|first8=Michael J.|last9=Liesch|first9=Jerrold M.|last10=Yudin|first10=Katherine|title=Pharmaceuticals from cultured algae|journal=Journal of Industrial Microbiology|date=April 1990|volume=5|issue=2–3|pages=113–123|doi=10.1007/BF01573860|s2cid=34480729|doi-access=free}} Cryptophycins were patented as antifungal agents with an unknown mechanism of action and subsequently identified as microtubule inhibitors.{{cite journal|last1=Smith|first1=CD|last2=Zhang|first2=X|last3=Mooberry|first3=SL|last4=Patterson|first4=GM|last5=Moore|first5=RE|title=Cryptophycin: a new antimicrotubule agent active against drug-resistant cells.|journal=Cancer Research|date=15 July 1994|volume=54|issue=14|pages=3779–84|pmid=7913408}} Closely related molecules were reported in the marine sponge Dysidea arenaria, which were first given the name arenastatins.{{cite journal|last1=KOBAYASHI|first1=Motomasa|last2=KUROSU|first2=Michio|last3=OHYABU|first3=Naoki|last4=WANG|first4=Weiqi|last5=FUJII|first5=Satoshi|last6=KITAGAWA|first6=Isao|title=The Absolute Stereostructure of Arenastatin A, a Potent Cytotoxic Depsipeptide from the Okinawan Marine Sponge Dysidea arenaria.|journal=Chemical & Pharmaceutical Bulletin|date=1994|volume=42|issue=10|pages=2196–2198|doi=10.1248/cpb.42.2196|doi-access=free}} 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.{{Cite journal|title = Metabolites from symbiotic bacteriaThis review is dedicated to Professor Axel Zeeck on the occasion of his 65th birthday.|journal = Natural Product Reports|date = 2004-01-01|volume = 21|issue = 4|doi = 10.1039/b310175b|first = Jörn|last = Piel|pmid=15282634|pages=519–38}} Nevertheless, study of the structure-activity relationships between the two subgroups of molecules led to improved understanding of their cytotoxic effects.{{cite book|last1=Cragg|first1=edited by Gordon M.|last2=Kingston|first2=David G.I.|last3=Newman|first3=David J.|title=Anticancer agents from natural products|date=2012|publisher=CRC Press|location=Boca Raton, FL|isbn=9781439813836|edition=2nd}}{{rp|230}}

Cryptophycins are potent microtubule inhibitors, with a mechanism of action similar to that of vinca alkaloids.{{cite journal|last1=Panda|first1=D|last2=DeLuca|first2=K|last3=Williams|first3=D|last4=Jordan|first4=MA|last5=Wilson|first5=L|title=Antiproliferative mechanism of action of cryptophycin-52: kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=4 August 1998|volume=95|issue=16|pages=9313–8|pmid=9689077|doi=10.1073/pnas.95.16.9313|pmc=21335|bibcode=1998PNAS...95.9313P|doi-access=free}}{{cite journal|last1=Panda|first1=D|last2=Himes|first2=RH|last3=Moore|first3=RE|last4=Wilson|first4=L|last5=Jordan|first5=MA|title=Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1.|journal=Biochemistry|date=21 October 1997|volume=36|issue=42|pages=12948–53|pmid=9335554|doi=10.1021/bi971302p}} Treatment of cells with cryptophycins depletes microtubules through interaction with tubulin, thereby preventing cell division.{{cite journal|last1=Zhang|first1=X.|title=Mechanism of Action of Cryptophycin|journal=Journal of Biological Chemistry|date=15 March 1996|volume=271|issue=11|pages=6192–6198|doi=10.1074/jbc.271.11.6192|pmid=8626409|doi-access=free}} Cryptophycins are capable of inducing apoptosis,{{cite journal|last1=Mooberry|first1=SL|last2=Busquets|first2=L|last3=Tien|first3=G|title=Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent.|journal=International Journal of Cancer|date=4 November 1997|volume=73|issue=3|pages=440–8|pmid=9359493|doi=10.1002/(sici)1097-0215(19971104)73:3<440::aid-ijc20>3.3.co;2-x|doi-access=free}} possibly through other mechanisms in addition to that mediated by microtubule inhibition.{{cite journal|last1=Drew|first1=L|last2=Fine|first2=RL|last3=Do|first3=TN|last4=Douglas|first4=GP|last5=Petrylak|first5=DP|title=The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells.|journal=Clinical Cancer Research|date=December 2002|volume=8|issue=12|pages=3922–32|pmid=12473608}}

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,{{cite journal|last1=Trimurtulu|first1=Golakoti|last2=Ohtani|first2=Ikuko|last3=Patterson|first3=Gregory M. L.|last4=Moore|first4=Richard E.|last5=Corbett|first5=Thomas H.|last6=Valeriote|first6=Frederick A.|last7=Demchik|first7=Lisa|title=Total Structures of Cryptophycins, Potent Antitumor Depsipeptides from the Blue-Green Alga Nostoc sp. Strain GSV 224|journal=Journal of the American Chemical Society|date=June 1994|volume=116|issue=11|pages=4729–4737|doi=10.1021/ja00090a020}} reached phase II clinical trials but was withdrawn due to side effects.{{cite journal|last1=Field|first1=Jessica J.|last2=Kanakkanthara|first2=Arun|last3=Miller|first3=John H.|title=Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function|journal=Bioorganic & Medicinal Chemistry|date=September 2014|volume=22|issue=18|pages=5050–5059|doi=10.1016/j.bmc.2014.02.035|pmid=24650703}}

Cryptophycins were first isolated from cyanobacteria but have subsequently been produced by chemical synthesis.{{cite journal|last1=Bolduc|first1=KL|last2=Larsen|first2=SD|last3=Sherman|first3=DH|title=Efficient, divergent synthesis of cryptophycin unit A analogues.|journal=Chemical Communications|date=22 May 2012|pmid=22617820|doi=10.1039/c2cc32417b|volume=48|issue=51|pages=6414|pmc=3494784}}{{cite journal|last1=Weiß|first1=C|last2=Bogner|first2=T|last3=Sammet|first3=B|last4=Sewald|first4=N|title=Total synthesis and biological evaluation of fluorinated cryptophycins.|journal=Beilstein Journal of Organic Chemistry|date=2012|volume=8|pages=2060–6|pmid=23209540|doi=10.3762/bjoc.8.231|pmc=3511040}} Chemoenzymatic syntheses have also been reported.{{cite journal|last1=Magarvey|first1=NA|last2=Beck|first2=ZQ|last3=Golakoti|first3=T|last4=Ding|first4=Y|last5=Huber|first5=U|last6=Hemscheidt|first6=TK|last7=Abelson|first7=D|last8=Moore|first8=RE|last9=Sherman|first9=DH|title=Biosynthetic characterization and chemoenzymatic assembly of the cryptophycins. Potent anticancer agents from cyanobionts.|journal=ACS Chemical Biology|date=15 December 2006|volume=1|issue=12|pages=766–79|pmid=17240975|doi=10.1021/cb6004307}}{{cite journal|last1=Ding|first1=Y|last2=Rath|first2=CM|last3=Bolduc|first3=KL|last4=Håkansson|first4=K|last5=Sherman|first5=DH|title=Chemoenzymatic synthesis of cryptophycin anticancer agents by an ester bond-forming non-ribosomal peptide synthetase module.|journal=Journal of the American Chemical Society|date=21 September 2011|volume=133|issue=37|pages=14492–5|pmid=21823639|doi=10.1021/ja204716f|pmc=3174474}}

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Category:Bacterial toxins

Category:Microtubule inhibitors