Synthesis and biological evaluation of 4β-acrylamidopodophyllotoxin congeners as DNA damaging agents

被引：24

作者：

Kamal, Ahmed ^{[1
]}

Suresh, Paidakula ^{[1
]}

Ramaiah, M. Janaki ^{[2
]}

Mallareddy, Adla ^{[1
]}

Kumar, Banala Ashwini ^{[1
]}

Raju, Paidakula ^{[1
]}

Gopal, J. Vinay ^{[2
]}

Pushpavalli, S. N. C. V. L. ^{[2
]}

Lavanya, A. ^{[2
]}

Sarma, Pranjal ^{[2
]}

Pal-Bhadra, Manika ^{[2
]}

机构：

[1] Indian Inst Chem Technol, Div Organ Chem, Hyderabad 500607, Andhra Pradesh, India

[2] Indian Inst Chem Technol, Ctr Chem Biol, Hyderabad 500607, Andhra Pradesh, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 15期

关键词：

Podophyllotoxin; Etoposide; Cell cycle analysis; Comet assay; gamma-H2AX staining; DNA strand breaks; Anticancer activity; TOPOISOMERASE-II INHIBITORS; ANTITUMOR AGENTS; POTENT INHIBITORS; 4-BETA-AMINOPODOPHYLLOTOXIN CONGENERS; CYTOTOXIC AGENTS; PODOPHYLLOTOXIN; DERIVATIVES; ANALOGS; DESIGN; CELLS;

D O I：

10.1016/j.bmc.2011.06.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of new 4 beta-acrylamidopodophyllotoxin derivatives (13a-o) were synthesized by coupling of substituted acrylic acids (10a-l and 11m-o) to the 4 beta-aminopodophyllotoxin. The synthesized derivatives 13a-o were evaluated for their cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). These podophyllotoxin conjugates have shown promising activity with GI(50) values ranging from <0.1 to 0.29 mu lM. Some of the compounds 13j, 13k and 13l that showed significant antiproliferative activity were also evaluated for related cytotoxic effects in MCF-7 cells, and compared to etoposide. These compounds (13j, 13k and 13l) showed G2/M cell cycle arrest and the apoptotic event was found to be due to both the single-strand DNA breaks as observed by comet assay as well as double-strand breaks as observed by the large accumulation of gamma H2AX foci. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4589 / 4600

页数：12

共 57 条

[1]

Ayres D. C., 1990, LIGNANS CHEM BBIOLOG

[2]

BOHRIN L, 1996, DRUG DISCOV TODAY, V1, P343

[3] ASYMMETRIC TOTAL SYNTHESIS OF (-)-PODOPHYLLOTOXIN [J].

BUSH, EJ ;

JONES, DW .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1993, (15) :1200-1201

[4]

Chen Y, 2005, ANTICANCER RES, V25, P4203

[5] Antitumor agents .163. Three-dimensional quantitative structure-activity relationship study of 4'-O-demethylepipodophyllotoxin analogs using the modified CoMFA/q(2)-GRS approach [J].

Cho, SJ ;

Tropsha, A ;

Suffness, M ;

Cheng, YC ;

Lee, KH .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (07) :1383-1395

[6]

Damayanthi Y, 1998, CURR MED CHEM, V5, P205

[7] COMPONENTS OF PODOPHYLLIN .5. THE CONSTITUTION OF PODOPHYLLOTOXIN [J].

HARTWELL, JL ;

SCHRECKER, AW .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1951, 73 (06) :2909-2916

[8] SYNTHESIS OF 2,4-DIAZA-4-DEOXYPODOPHYLLOTOXIN, A NEW ANALOG OF PODOPHYLLOTOXIN POSSESSING ANTITUMOR-ACTIVITY [J].

HITOTSUYANAGI, Y ;

NAKA, Y ;

YAMAGAMI, K ;

FUJII, A ;

TAHARA, T .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1995, (01) :49-50

[9] SYNTHESIS OF 4-THIA-2-AZAPODOPHYLLOTOXIN, A NEW ANALOG OF THE ANTITUMOR LIGNAN PODOPHYLLOTOXIN [J].

HITOTSUYANAGI, Y ;

KOBAYASHI, M ;

TAKEYA, K ;

ITOKAWA, H .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1995, (11) :1387-1390

[10]

Huang S. T., 1999, J PHARM RES, V16, P997

← 1 2 3 4 5 6 →