G Model
CCLET-3255; No. of Pages 4
Chinese Chemical Letters
Original article
Synthesis and antitumor activity of
a-aminophosphonate derivatives
containing thieno[2,3-d]pyrimidines
Yan-Chun Guo a, Jing Li a, Jiao-Li Ma a, Zhi-Ran Yu a, Hai-Wei Wang a, Wen-Juan Zhu a,
a,b
Xin-Cheng Liao a, , Yu-Fen Zhao
*
a The College of Chemistry and Molecular Engineering, The Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou
University, Zhengzhou 450052, China
b Department of Chemistry, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University,
Xiamen 361005, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Two series of thieno[2,3-d]pyrimidine derivatives were designed and synthesized, in which bioactive a-
Received 13 November 2014
Received in revised form 19 December 2014
Accepted 6 March 2015
Available online xxx
aminophosphonate subunits were introduced at the N3 position through an N–N bond connection. The
in vitro cytotoxic activity of the novel compounds was tested against human esophageal carcinoma cells
(EC109), human hepatocarcinoma cells (HepG2), human gastric carcinoma cells (MGC-803),
respectively, by the MTT method. The evaluation results revealed that compounds 6mb, 6mf, 6mg,
6nd and 6nh exerted the most potent inhibition against HepG2, MGC-803 and EC109 cells, respectively.
In particular, compound 6mg presented excellent inhibitory effect against HepG2 (91.2%) and MGC-803
(94.4%) cells.
Keywords:
a-Aminophosphonate derivatives
Thieno[2,3-d]pyrimidine
Synthesis
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Antitumor
1. Introduction
or fluorine moiety containing a-aminophosphonates [24–27] were
proved to have high antitumor activity.
It is well known that fused pyridines and thienopyrimidines
have many valuable pharmacological properties, such as antiox-
idative [1,2], antimalarial [3,4], antibacterial [5], and antiviral
effects [6]. The pyrimidine-based derivatives, e.g. thieno[2,3-
d]pyrimidines, were proved to have pharmacological and thera-
peutic properties in medicinal chemistry, such as anti-inflamma-
tory [7], antibacterial [8,9], antifungal [10,11], antitumor [12],
antidepressant [13], antiplatelet [14], antihypertensive [15],
herbicidal [16] and plant growth regulatory [17] properties.
Based on the concept of bioisosterism and inspired by the above
observations, we were led to the proposal to incorporate
thieno[2,3-d]pyrimidine ring into the
pounds, to construct novel classes of thieno[2,3-d]pyrimidine
moiety containing -aminophosphonate derivatives, and to
evaluate their antitumor activity. Therefore, two series of such
compounds, incorporating the -aminophosphonate and the
a-aminophosphonate com-
a
a
thieno[2,3-d]pyrimidines, were designed and synthesized and
their antitumor properties were investigated.
As phosphorus analogs of
a
-amino acids and their esters,
a
-
Twenty-two new diethyl or diisopropyl [(3-substituted or 4-
substituted or 2,4-disubstituted) (2-methyl-6-ethyl-4-oxo-4-H-
thieno[2,3-d]pyrimidin-3-yl-amino) methyl] phosphonates were
synthesized and their in vitro antitumor activity under cell
membrane conditions were evaluated by the MTT method.
Compounds 6ma-6mk and 6na-6nk, as well as the intermediates
4a-4k, were tested for their anti-proliferation activity against
three human cancer cell lines (EC109, HepG2 and MGC-803) at
different concentrations. This represents the first report about
the synthesis and in vitro antitumor activity evaluation of
aminophosphonates have received much attention owing to their
potential biological activities such as antibacterial, anticancer, as
well as insecticidal and herbicidal properties, [18–22] and were
investigated as starting materials for the syntheses of phospho-
nopeptides. Moreover, if the aminophosphonate subunit was
suitably embedded into potential antitumor agents, it could
effectively improve their bioactivity [23], e.g. benzothiazole moiety
thieno[2,3-d]pyrimidines
derivatives.
containing
a-aminophosphonate
*
Corresponding author.
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Y.-C. Guo, et al., Synthesis and antitumor activity of
a-aminophosphonate derivatives containing