Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity.
Anticancer Agents Med Chem
; 18(5): 747-756, 2018.
Article
em En
| MEDLINE
| ID: mdl-29366427
ABSTRACT
BACKGROUND:
4-Substitutedaminoquinazoline scaffolds were reported to possess potent cytotoxic and EGFR inhibitory activity such as gefitinib (Iressa), erlotinib (Tarceva) and tandutinib.OBJECTIVE:
Synthesis of novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives as bioisosters of 4-substitutedaminoquinazoline derivatives with potential cytotoxic and EGFR inhibitory activity.METHODS:
Novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives 4a-i and 5a-c were synthesized via reacting corresponding 4-chlorothieno[2,3-d]pyrimidine derivatives 3a-c with N-methylpiperazine, morpholine, N-phenylpiperazine or 1,3-propanediamine. Six compounds (2a, 4d, 4e, 5a-c) were selected by the National Cancer Institute (USA) for evaluating their cytotoxic activity using 60 different human tumor cell lines using a single dose (10-5 Molar). The rest of the synthesized compounds (2b, 2c, 3a-c, 4a-c and 4f-i) were subjected to screening against T47D breast cancer cell line using a single dose (10-5 Molar) at Pharmacology lab., Cancer biology lab., Egyptian National Institute. Moreover, compounds 2a and 4b-e were subjected to further evaluation by IC50 determination. Finally, the inhibition of epidermal growth factor receptor (EGFR) was then investigated for the most active compounds 2a and 4d.RESULTS:
Compounds 2a and 4b-e showed significant cytotoxic activity. Compound 2a was more potent than doxorubicin against lung cancer cell line A549 with IC50 = 13.40 µM and comparable activity against MCF7. Compound 4d exhibited more potent activity than Doxorubicin against prostate PC3 (IC50 = 14.13 µM) while showed comparable activity against MCF7 and T47D.CONCLUSION:
4-Substitutedaminothieno[2,3-d]pyrimidine is a promising backbone for the design and synthesis of potent cytotoxic leads.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Inibidores de Proteínas Quinases
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Anticancer Agents Med Chem
Assunto da revista:
ANTINEOPLASICOS
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Egito