Title:Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity
VOLUME: 18 ISSUE: 5
Author(s):Mina E. Adly, Ehab M. Gedawy*, Afaf A. El-Malah and Farag A. El-Telbany
Affiliation:Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562
Keywords:Thieno[2, 3-d]pyrimidines, synthesis, cytotoxicity, EGFR, gefitinib (Iressa), erlotinib, tandutinib.
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.
