新型噻吩并[2,3-d]嘧啶衍生物的合成及其细胞毒性和 EGFR 抑制活性评价。

Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity.

机构信息

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.

出版信息

Anticancer Agents Med Chem. 2018;18(5):747-756. doi: 10.2174/1871520618666180124121441.

DOI:10.2174/1871520618666180124121441

PMID: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.

摘要

背景

4-取代氨基喹唑啉支架被报道具有有效的细胞毒性和 EGFR 抑制活性，如吉非替尼（Iressa）、厄洛替尼（Tarceva）和坦度替尼。

目的

合成新型 4-取代氨基噻吩并[2,3-d]嘧啶衍生物，作为 4-取代氨基喹唑啉衍生物的生物等排物，具有潜在的细胞毒性和 EGFR 抑制活性。

方法

通过将相应的 4-氯噻吩并[2,3-d]嘧啶衍生物 3a-c 与 N-甲基哌嗪、吗啉、N-苯基哌嗪或 1,3-丙二胺反应，合成了新型 4-取代氨基噻吩并[2,3-d]嘧啶衍生物 4a-i 和 5a-c。根据美国国立癌症研究所（NCI）的评估，使用 60 种不同的人类肿瘤细胞系，采用单剂量（10-5 摩尔），选择了 6 种化合物（2a、4d、4e、5a-c）进行细胞毒性活性评价。其余合成的化合物（2b、2c、3a-c、4a-c 和 4f-i）在药理学实验室和癌症生物学实验室，用单剂量（10-5 摩尔）对 T47D 乳腺癌细胞系进行了筛选。此外，还通过 IC50 测定进一步评价了化合物 2a 和 4b-e。最后，研究了最活跃的化合物 2a 和 4d 对表皮生长因子受体（EGFR）的抑制作用。

结果

化合物 2a 和 4b-e 表现出显著的细胞毒性活性。化合物 2a 对肺癌细胞系 A549 的抑制活性比多柔比星更强，IC50=13.40 μM，对 MCF7 的活性相当。化合物 4d 对前列腺癌 PC3 的抑制活性比多柔比星更强，IC50=14.13 μM，对 MCF7 和 T47D 的活性相当。