Bioorganic & Medicinal Chemistry 9 (2001) 1707–1711
A Series of Enediynes as Novel Inhibitors of Topoisomerase I
Chi-Fong Lin,a Pei-Chen Hsieh,a Wen-Der Lu,a Huey-Fen Chiub and Ming-Jung Wua,*
aSchool of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
bGraduate Insititute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
Received 14 December 2000; accepted 26 February 2001
Abstract—A series of acyclic enediynes, 2-((6-substituted)-3-hexen-1,5-diynyl)benzonitriles (8–11), display potent inhibition against
topoisomerase I without the formation of active biradical intermediates and show inhibitory activity against topoisomerase I at
10 mM, which is five times that of camptothecin from the results of agarose gel electrophoresis. # 2001 Elsevier Science Ltd. All
rights reserved.
Introduction
under 37 ꢀC (path b). An overview of the possible
mechanisms which anticancer drugs would proceed. The
most probable pathway of 2-(6-substituted-3(Z)-hexen-
1,5-diynyl)benzonitriles to induce the death of cancer
cells is the physiological enzyme inhibitors, especially
the topological enzymes; the topoisomerase, which was
essential for DNA replication, transcription, repair,
recombination, and chromosome segregation.4 Human
topoisomerase I (topo I) is a protein consisting of 765
amino acids, reconstituted from two fragments of the
protein involving three subdomain cores, the COOH-
terminal domains, and a positively charged surface,
complexed either covalently or noncovalently with a 22-
base pair DNA oligonucleotide. Several potent antic-
ancer therapies achieve their effects by pharmacological
inhibition of either topo I or II.5 However, cleavage of
duplex DNA by topo I is monomeric and transiently
includes nucleophilic attack by a catalytic tyrosine resi-
due on the scissile phosphodiester bond that culminates
in the formation of a covalent bond between the enzyme
and one end of the broken strand. Topo I is also the sole
target of the camptothecin family of anticancer drugs
which had two analogues of camptothecin, topotecan,
and irinotecan, has been used successfully in the treat-
ment of several human cancers.6,7 Besides camptothecin
A series of alkaloids containing enediyne cores which
were isolated from Streptomyces have manifold biologi-
cal activities1 owing to the generation of radicals. Sev-
eral biologically active synthetic enediynes are also
observed in the formation of radicals, However, besides
formation of biradical intermediates, there is little
attention to other feasible reaction modes by which
enediynes could act and their relative biological activ-
ities that enediynes could exhibit, though reports of
novel biradical reactions have begun to surface.2 There
is no investigation describing that enediynes could
deactivate topoisomerase I without the formation of
radical intermediates. During a routine screening of
cytotoxicity, it was surprising that a series of 2-(6-sub-
stituted-3(Z)-hexen-1,5-diynyl)benzonitriles
showed
potent cytotoxicity with a KB cell (see Table 1). The
high activity which 2-(6-substituted-3(Z)-hexen-1,5-diy-
nyl) benzonitriles possessed promoted our studies
toward this unexpected biological behavior.
It is considered that these molecules comprise an ene-
diyne structure but unlike the accustomed mode of ene-
diynes3 which generate biradicals and facilitate the
decease of cells (Scheme 1), there is no initiating factor
to promote the enediynes to form active biradicals via
Myers cycloaromatization (path a). Similarly, according
to Bergman’s reports, the acyclic enediynes cannot
cycloaromatize to produce biradical intermediates
Table 1. Cytotoxic of 2-(6-substituted-3(Z)-hexen-1,5-diynyl) benzo-
nitriles (IC50)
Compound/cell
KB (mM)
Hep2,2,15 (mM)
7
8
9
10
À02.1
<10
<10À2
<10À2
>10
>10
17
*Corresponding author. Tel.:+886-7-312-1101, ext 2220; fax: +886-
731-5339; e-mail: mijuwu@cc.kmu.edu.tw
>10
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00081-5