Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents

被引：73

作者：

Kamal, Ahmed ^{[1
]}

Reddy, J. Surendranadha ^{[1
]}

Ramaiah, M. Janaki ^{[1
]}

Dastagiri, D. ^{[1
]}

Bharathi, E. Vijaya ^{[1
]}

Azhar, M. Ameruddin ^{[1
]}

Sultana, Farheen ^{[1
]}

Pushpavalli, S. N. C. V. L. ^{[1
]}

Pal-Bhadra, Manika ^{[1
]}

Juvekar, Aarti ^{[2
]}

Sen, Subrata ^{[2
]}

Zingde, Surekha ^{[2
]}

机构：

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

[2] Adv Ctr Treatment Res & Educ Canc, Navi Mumbai, India

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 09期

关键词：

Pyrrolobenzodiazepine; 3,5-Diaryl-isoxazoline/isoxazole; p53; Cytochrome c; Procaspase-3; DNA-BINDING AFFINITY; ANTITUMOR-ACTIVITY; COMBRETASTATIN A-4; HYBRID MOLECULES; CYTOTOXICITY; MITOCHONDRIA; INHIBITION; APOPTOSIS; ANALOGS; ABILITY;

D O I：

10.1016/j.ejmech.2010.05.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI(50) values in the range of <0.1-3.6 mu M. Some of these PBD conjugates (6a-c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated intrinsic pathway, leading to release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent apoptotic cell death. Hence these PBD conjugates with 6a being the most potent one could be be taken up for preclinical studies either alone or in combination with existing therapies. (C) 2010 Elsevier Masson SAS. All rights reserved.

引用

页码：3924 / 3937

页数：14

共 34 条

[1]

ALEXIS AB, 2000, PNAS, V100, P7977

[2] Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1,4]benzodiazepine and minor-groove-binding oligopyrrole carriers [J].

Baraldi, PG ;

Balboni, G ;

Cacciari, B ;

Guiotto, A ;

Manfredini, S ;

Romagnoli, R ;

Spalluto, G ;

Thurston, DE ;

Howard, PW ;

Bianchi, N ;

Rutigliano, C ;

Mischiati, C ;

Gambari, R .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (25) :5131-5141

[3]

Carlson BA, 1996, CANCER RES, V56, P2973

[4] Design and synthesis of novel pyrrolo[2,1-c][1,4]benzodiazepine-lexitropsin conjugates [J].

Damayanthi, Y ;

Reddy, BSP ;

Lown, JW .

JOURNAL OF ORGANIC CHEMISTRY, 1999, 64 (01) :290-292

[5] DC-81-Indole conjugate agent induces mitochondria mediated apoptosis in human melanoma A375 cells [J].

Hu, Wan-Ping ;

Yu, Hsin-Su ;

Sung, Ping-Jyun ;

Tsai, Feng-Yuan ;

Shen, Yu-Kai ;

Chang, Long-Sen ;

Wang, Jeh-Jeng .

CHEMICAL RESEARCH IN TOXICOLOGY, 2007, 20 (06) :905-912

[6] PYRROLO[1,4]BENZODIAZEPINE ANTITUMOR ANTIBIOTICS - RELATIONSHIP OF DNA ALKYLATION AND SEQUENCE SPECIFICITY TO THE BIOLOGICAL-ACTIVITY OF NATURAL AND SYNTHETIC COMPOUNDS [J].

HURLEY, LH ;

RECK, T ;

THURSTON, DE ;

LANGLEY, DR ;

HOLDEN, KG ;

HERTZBERG, RP ;

HOOVER, JRE ;

GALLAGHER, G ;

FAUCETTE, LF ;

MONG, SM ;

JOHNSON, RK .

CHEMICAL RESEARCH IN TOXICOLOGY, 1988, 1 (05) :258-268

[7] Cytochrome C-mediated apoptosis [J].

Jiang, XJ ;

Wang, XD .

ANNUAL REVIEW OF BIOCHEMISTRY, 2004, 73 :87-106

[8] Isoxazole-type derivatives related to combretastatin A-4, synthesis and biological evaluation [J].

Kaffy, Julia ;

Pontikis, Renee ;

Carrez, Daniele ;

Croisy, Alain ;

Monneret, Claude ;

Florent, Jean-Claude .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (12) :4067-4077

[9] Design, synthesis, and evaluation of new noncross-linking pyrrolobenzodiazepine dimers with efficient DNA binding ability and potent antitumor activity [J].

Kamal, A ;

Ramesh, G ;

Laxman, N ;

Ramulu, P ;

Srinivas, O ;

Neelima, K ;

Kondapi, AK ;

Sreenu, VB ;

Nagarajaram, HA .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (21) :4679-4688

[10] An efficient reduction of azides to amines:: synthesis of DNA interactive pyrrolo[2,1-c][1,4]benzodiazepines [J].

Kamal, A ;

Laxman, E ;

Arifuddin, M .

TETRAHEDRON LETTERS, 2000, 41 (40) :7743-7746

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