ORGANIC
LETTERS
2010
Vol. 12, No. 5
1064-1067
“Clicktophycin-52”: A Bioactive
Cryptophycin-52 Triazole Analogue
Markus Nahrwold, Tobias Bogner, Stefan Eissler, Spart Verma, and
Norbert Sewald*
Bielefeld UniVersity, Department of Chemistry, Organic and Bioorganic Chemistry,
UniVersita¨tsstrasse 25, 33615 Bielefeld, Germany
Received January 8, 2010
ABSTRACT
An endocyclic trans-amide linkage within the macrocyclic antitumor agent cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring.
Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated “click”-cyclization. Compared to
cryptophycin-52, in vitro cytotoxicity of “clicktophycin-52” against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced.
Since the CuI catalyzed azide-alkyne coupling was discovered
by the workgroups of Meldal and Sharpless,1 this so-called
“click”-reaction found numerous applications.2-4 Although size
and dipole moment of the metabolically inert 1,4-disubsti-
tuted triazole ring are larger compared to a trans-amide
bond,2 the overall physicochemical properties are similar
enough to enable these triazoles to act as trans-amide
mimetics.3,5-12 The bioisosterism has been exemplified by
triazole analogues of a matrix metalloprotease inhibitor,6 of
the immuno stimulating natural compound R-galactosylcer-
amide,7 and of capsaicin in its role as agonist of the vanilloid-
receptor TRPV1.9 Further examples are triazole analogues
of the tyrosinase inhibitor cyclo-[Pro-Tyr-Pro-Val],10 of the
histone deacetylase inhibitor apicidin,8 and of peptides
containing the pharmacophoric residues of somatostatin.11
Moreover, X-ray analysis revealed the triazole ring within
an analogue of the HIV-1-protease inhibitor amprenavir to
interact with the enzyme in the same way as an amide bond
in the parent compound.12
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10.1021/ol1000473 2010 American Chemical Society
Published on Web 02/04/2010