iv. mezioborové setkênè mladðch biologů ... - Chemické listy

Chem. Listy 98, 271 – 314 (2004) IV. Amerika 2004.
ANTICANCER DRUG ELLIPTICINE FORMS DNA
ADDUCTS IN VIVO; A NOVEL MODE OF ITS
ANTINEOPLATIC ACTION
DAGMAR AIMOVÁ and MARIE STIBOROVÁ
Department of Biochemistry, Faculty of Science, Charles
University, Albertov 2030, 128 40 Prague 2, The Czech
Republic
dagmar_aimova@seznam.cz
Ellipticine is a potent antineoplastic agent, whose mode
of action is considered to be based mainly on DNA
intercalation and/or inhibition of topoisomerase II. We found
that ellipticine also forms covalent DNA adducts in vitro and
that the formation of DNA adducts is dependent on the
activation of ellipticine by cytochrome P450 (CYP) (cit. 1 ).
This implicates the potential importance of several CYPs in
producing more active ellipticine metabolite(s). Here, we
investigated the capacity of ellipticine to form DNA adducts in
vivo. Male Wistar rats were treated with ellipticine, and DNA
from various organs was analyzed by
32 P-postlabeling.
Ellipticine-specific DNA adduct patterns, similar to those
found in vitro, were detected in most test organs. The highest
level of DNA adducts was found in liver, followed by spleen,
lung, kidney, heart and brain. One major and one minor
ellipticine-DNA adducts were found in DNA of all these
organs of rats exposed to ellipticine. Besides these, two or
three additional adducts were detected in DNA of liver,
kidney, lung and heart. The predominant adduct formed in rat
tissues in vivo was identical to the deoxyguanosine adduct
generated in DNA by ellipticine in vitro. Correlation studies
showed that the formation of this major DNA adduct in vivo is
mediated by CYP3A1- and CYP1A-dependent reactions. The
additional aim of the present work was to study whether
ellipticine could influence the expression of the major CYPs
participating in its metabolism. An expression of CYP1A1/2
proteins in liver of rats of both sexes is strongly induced by
treatment of animals with ellipticine. The expression levels of
CYP1A1/2 in treated rats are one order of magnitude higher
than those in control animals. The CYP1A1/2 induction is
strongly dependent on concentration of ellipticine applied to
experimental animals and on the time of their exposition. The
induction of other isoforms of cytochromes P450 (CYP2B,
2E1, 3A) was negligible. The results presented here are the
first report showing the formation of CYP-mediated covalent
DNA adducts by ellipticine in vivo, and confirm the formation
of covalent DNA adducts as a new mode of ellipticine action.
In addition, they indicate that a long-term treatment of humans
with ellipticine might stimulate its pharmacological efficiency
against cancer diseases.
Supported by Grant Agency of the Czech Republic (grant
203/01/0996) and the Ministry of Education of the Czech
Republic (grant MSM 1131 00001).
REFERENCES
1) Stiborová M., Bieler C. A., Wiessler M., Frei E.:
Biochem. Pharmacol. 62, 1675 (2001).
VYUŽITÍ DIASTEREOSELEKTIVNÍ [2+2+2]
CYKLOIZOMERACE TRIYNŮ PRO PŘÍPRAVU
HELIKÁLNĚ CHIRÁLNÍCH LÁTEK
ZUZANA ALEXANDROVÁ, IRENA G. STARÁ, FILIP
TEPLÝ, PETR SEHNAL, IVO STARÝ, DAVID ŠAMAN a
MILOŠ BUDĚŠÍNSKÝ
Ústav organické chemie a biochemie AV ČR, Flemingovo n. 2,
166 10 Praha 6
alexa@uochb.cas.cz
V minulosti jsme vyvinuli obecný způsob přípravy
helikálně chirálních látek, který je založen na intramolekulární
[2+2+2] cykloizomeraci aromatických triynů za katalýzy 1,2
kobaltem (I) či niklem (0). Nedávno jsme pozorovali, že
centrum chirality ve výchozím triynu může řídit
stereoselektivitu cyklizace 3 . Tímto způsobem je pak
kontrolována helicita produktu.
S využitím této syntetické metodologie jsme připravili
neracemickou helikálně chirální látku (P,1S)-(+)-1, jejíž
struktura je odvozená od helicenů 4 . Syntéza vychází z
dostupného bromjodidu 2. V prvním kroku byl působením
hydridu draselného generován alkoholát odvozený od (2S)-(-)-
3, který byl poté alkylován bromjodidem 2 za vzniku látky
(1S)-(-)-4. Sonogashirův coupling diacetylenu 5 s
naftyljodidem (1S)-(-)-4 a následná desilylace účinkem
tetrabutylamoniumfluoridu vedly k požadovanému triynu (1S)-
(-)-6. Syntetická sekvence byla završena intramolekulární
[2+2+2] cykloizomerací triynu (1S)-(-)-6 za katalýzy
komplexem kobaltu, a byla tak získána požadovaná helikálně
chirální látka (P,1S)-(+)-1 .
2
I
O
*
(P,1S)-(+)-1
R:
Br
R
HO
*
(2S)-(-)-3
a
d
R
(1S)-(-)-4
b, c
I
5
(1S)-(-)-6
(a) KH, THF; (b) Pd(PPh 3 ) 4 , CuI (kat.); (c) Bu 4 NF; (d)
CpCo(CO) 2 (1 ekv.)
O
O
*
*
R
R
TIPS
273