Journal of Medicinal Chemistry
BRIEF ARTICLE
the Supporting Information). Of these four compounds, 3d
demonstrated excellent cytotoxic potencies and greater lethality
for neoplasms than normal cells, thereby confirming it to be an
excellent lead molecule for preclinical evaluations.
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’ CONCLUSIONS
1-[3-(2-Hydroxyethylthio)propanoyl]-3,5-bis(benzylidene)
piperidin-4-ones 3, in particular 3d and 3e, are a novel cluster of
tumor-specific cytotoxins. 3d and 3e display excellent growth-
inhibiting properties against a number of human cancer cell lines,
are especially effective against colon cancers and leukemic cells,
and are more potent cytotoxins than 5-fluorouracil and melpha-
lan. The increased toxicity of 3aꢀe toward certain neoplasms
compared with normal cells was revealed; in particular 3d and 3e
demonstrate greater toxicity to the tumors. The observation that
3d and 3e exert their lethal effects in different ways depending on
the cell line under consideration probably contributes signifi-
cantly to them being tumor-selective cytotoxins. Doses up to and
including 300 mg/kg 3bꢀe were administered to mice without
causing fatalities or neurotoxicity, which further enhances their
potential for development.
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’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic procedures, biological
b
methods, evaluation of druglike properties of 3aꢀe. This material
(12) Boyd, M. R.; Paull, K. D. Some practical considerations and
applications of the National Cancer Institute in vitro anticancer drug
discovery screen. Drug Dev. Res. 1995, 34, 91–109.
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(14) Remers, W. A. Antineoplastic Agents. In Wilson and Gisvold's
Textbook of Organic Medicinal and Pharmaceutical Chemistry, 10th ed.;
Delgado, J. N., Remers, W. A., Eds.; Lippincott-Raven: Philadelphia, PA,
1998; p 367.
’ AUTHOR INFORMATION
Corresponding Author
*For U.D.: phone, þ1-306-966-6358; fax, þ1-306-966-6377;
e-mail, umashankar.das@usask.ca. For J.R.D.: phone, þ1-306-
966-6331; fax, þ1-306-966-6377; e-mail, jr.dimmock@usask.ca.
’ ACKNOWLEDGMENT
(15) Greenspan, E. M.; Bruckner, H. W. Aspects of Clinical Pharma-
cology. In Clinical Cancer Chemotherapy; Greenspan, E. M., Ed.; Raven
Press: New York, 1975; p 37.
(16) Quinn, F. R.; Milne, G.W. A. Toxicities derived from anti-tumor
screening data. Fundam. Appl. Toxicol. 1986, 6, 270–277.
(17) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Experimental and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv. Drug
Delivery Rev. 1997, 23, 3–25.
The following agencies are thanked for providing support for
this study: Canadian Institutes of Health Research for an
operating grant to J.R.D., Ministry of Education, Science, Sports
and Culture for a Grant-in-Aid (No. 19592156) to H.S., the
Geconcerteerde Onderzoeksacties (GOA 05/19), which pro-
vided funds to J.B., U.S. National Cancer Institute, which
generated the data in Table 2, and J. P. Stables and the National
Institute of Neurological Disorders and Stroke, which undertook
the toxicity evaluations in rodents. L. Van Berckelaer of Rega
Institute, Belgium, kindly carried out the Molt 4/C8, CEM and
L1210 bioassays. The authors thank Beryl McCullough and
Gwen Korte who typed several drafts of the manuscript.
(18) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward,
K. W.; Kopple, K. D. Molecular properties that influence the oral
bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615–2623.
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