Journal of Medicinal Chemistry
BRIEF ARTICLE
On the basis of these results, 12 was selected for in vivo PK
evaluation in rats. Compound 12/1 (dissolved in PEG 400/dehy-
drated ethanol/Solutol = 20:30:50) was administered to rats intrave-
nously (iv) at 5 mg/kg body weight and orally at 20 mg/kg body
weight. Blood samples were taken, and the plasma was analyzed for
concentration of 12/1 using an LC-MS/MS system. The 7-azain-
dole 12 displayed drug exposure similar to that of indole 1 after
intravenous (iv) administration (Table 2). Most interestingly 12
showed improved oral bioavailability (F = 35%) when compared
to 1 (F = 9.5%). Overall, these results suggest that the 7-azaindole
12 has potential for development as an orally bioavailable antic-
ancer agent that could serve as a backup drug candidate for 1.
’ ACKNOWLEDGMENT
The study was financially supported by the National Health
Research Institutes and the National Science Council (Grant
NSC-95-2113-M-400-001-MY3), Taiwan, ROC. We thank Mark
Swofford for helping with the English editing.
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’ CONCLUSIONS
5,6-Fused bicyclic heteroaromatic scaffolds that bear essential
structural features for anticancer activity based on the lead 1 were
designed. The 5,6-fused heteroaromatic cores 2-12 were
synthesized in a total of two to seven steps from six-membered
rings (pyridine/benzene) or commercially available 5,6-fused
heteroaromatic cores. Appropriate placement of both the meth-
oxy and trimethoxybenzoyl groups (prerequisite groups for
anticancer activity) in the core structures of 2-11 proved
synthetically challenging and was not always as straightforward
as envisaged; alternative synthetic strategies were developed,
when necessary, to overcome difficulties encountered. Among
the compounds synthesized, presence of an NH group in the first
position of the heteroaromatic core resulted in potent anticancer
activity and presence of an N atom in the seventh position
improved metabolic stability. The 7-azaindole 9 and pyrazolo-
[1,5-b]pyridazine 10 core containing compounds showed potent
anticancer activity and greater in vitro metabolic stability than the
indole (1) core. Most interestingly, 7-azaindole core 12 with
6-methyl substitution showed potent in vitro anticancer activity
with improved metabolic stability, solubility, and oral bioavail-
ability (F) compared with 1. Therefore, the scaffold-hopping
drug-design strategy has provided us with backup drug candidate
12, an orally bioavailable anticancer agent, with altered drug
properties and broader IP rights.14
’ EXPERIMENTAL SECTION
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tive inhibitors of glycogen synthase kinase 3 with good cellular efficacy.
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(6-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3,4,5-trimeth-
oxyphenyl)methanone (12). Compound 12 was synthesized in
66% yield from 45 and 3,4,5-trimethoxybenzoyl chloride, using AlCl3.
See Supporting Information for details.
(12) Wu, Y. S.; Coumar, M. S.; Chang, J. Y.; Sun, H. Y.; Kuo, F. M.;
Kuo, C. C.; Chen, Y. J.; Chang, C. Y.; Hsiao, C. L.; Liou, J. P.; Chen,
C. P.; Yao, H. T.; Chiang, Y. K.; Tan, U. K.; Chen, C. T.; Chu, C. Y.; Wu,
S. Y.; Yeh, T. K.; Lin, C. Y.; Hsieh, H. P. Synthesis and evaluation of
3-aroylindoles as anticancer agents: metabolite approach. J. Med. Chem.
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(13) Liou, J. P.; Mahindroo, N.; Chang, C. W.; Guo, F. M.; Lee,
S. W.; Tan, U. K.; Yeh, T. K.; Kuo, C. C.; Chang, Y. W.; Lu, P. H.; Tung,
Y. S.; Lin, K. T.; Chang, J. Y.; Hsieh, H. P. Structure-activity relationship
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’ ASSOCIATED CONTENT
S
Supporting Information. Docking and tubulin polymer-
b
ization inhibition of 1, 3, 9, and 12; schemes for 10 and 11;
synthesis and spectral data for 2-12; and in vitro and in vivo
biological evaluation protocols. This material is available free of
’ AUTHOR INFORMATION
(14) Hsieh, H.-P.; Chao, Y.-S.; Liou, J.-P.; Chang, J.-Y.; Tung, Y.-S.
Anti-Tumor Compounds. US7456289, 2008.
Corresponding Author
*Phone, þ886-37-246-166, ext 35708. Fax: þ886-37-586-456.
E-mail: hphsieh@nhri.org.tw.
Author Contributions
bThese authors contributed equally to this work.
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dx.doi.org/10.1021/jm101027s |J. Med. Chem. 2011, 54, 3076–3080