Optimization of Naphthalimide-imidazoacridone with Potent Antitumor Activity Leading to Clinical Candidate (HKH40A, RTA 502)

Optimization of Naphthalimide-imidazoacridone with Potent Antitumor Activity Leading to Clinical Candidate (HKH40A, RTA 502)

Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b that not only inhibited the growth of many tumor cell lines, but caused rapid apoptosis. Unlike the parent compound, 7b is toxic to both p53 positive and negative cancer cells. It has potent in vivo activi...

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Veröffentlicht in:Journal of medicinal chemistry 2007-11, Vol.50 (23), p.5557-5560
Hauptverfasser: Hariprakasha, Humcha K, Kosakowska-Cholody, Teresa, Meyer, Colin, Cholody, Wieslaw M, Stinson, Sherman F, Tarasova, Nadya I, Michejda, Christopher. J
Format: Artikel
Sprache:eng
Schlagworte:
Acridones - chemical synthesis
Acridones - chemistry
Acridones - pharmacokinetics
Acridones - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Apoptosis
Biological and medical sciences
Cell Line, Tumor
Drug Screening Assays, Antitumor
General aspects
Humans
Medical sciences
Mice
Mice, Nude
Naphthalimides - chemical synthesis
Naphthalimides - chemistry
Naphthalimides - pharmacokinetics
Naphthalimides - pharmacology
Neoplasm Transplantation
Pharmacology. Drug treatments
Rats
Structure-Activity Relationship
Tissue Distribution
Transplantation, Heterologous
Tumor Suppressor Protein p53 - metabolism
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Beschreibung
Zusammenfassung:Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b that not only inhibited the growth of many tumor cell lines, but caused rapid apoptosis. Unlike the parent compound, 7b is toxic to both p53 positive and negative cancer cells. It has potent in vivo activity against xenografts of human colon and pancreatic tumors in athymic mice.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm7009777