Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage

Kapuriya, Naval; Kapuriya, Kalpana; Zhang, Xiuguo; Chou, Ting‐Chao; Kakadiya, Rajesh; Wu, Yu Tse; Tsai, Tung Hu; Chen, Yuting; Lee, Te‐Chang; Shah, Anamik; Naliapara, Yogesh T.; Su, Tingwei

doi:10.1016/j.bmc.2008.04.024

Cited by 58 publications

(31 citation statements)

References 24 publications

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“…[11][12][13] Among them, 3a-aza-cyclopenta [a] indene derivatives were designed and synthesized based on the mechanism of action of mitomycin C, bis-carbamates and pyrrolizidine. 13 These compounds have potent cytotoxic effects on a variety of cancer cell lines in vitro as well as potent therapeutic efficacy in inhibiting human breast tumor MX-1 cells in xenografted mice.…”

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confidence: 99%

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Sanjiv

Suman

et al. 2011

Intl Journal of Cancer

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Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO-1090, bis(hydroxymethyl)-3a-aza-cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (c-H2AX focus formation). Following DNA damage, BO-1090 induced G1/S-phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO-1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO-1090 significantly suppressed tumor growth in comparison to control mice. BO-1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO-1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0-1090 may have potential as a treatment for oral cavity cancer.Oral cavity cancer involving the lesions occurred in the tongue, oropharynx and floor of the mouth is a prevalent type of cancer in developing countries such as India, Pakistan, Bangladesh and Taiwan. 1 In south-central Asia, it is the third-most common cancer, with an average incidence rate of 1 to 10 per 100,000 people. The incidence of oral cancer is also increasing in developed countries. 2 The treatments of oral cancer include surgery, radiation or chemotherapy, depending on the stage and nature of the tumor. 3,4 Unfortunately, only marginal improvement is seen in many patients, and a complete cure is often not achieved. Half of the patients diagnosed with oral cancer succumb to death within 5 years, and for those who survive, the quality of life remains poor. 1 Thus, development of a drug specific for oral cavity cancer is needed so that substantial improvement in treatment can be achieved.The cytotoxic and antitumor properties of alkylating agents are due to their ability to covalently bind to DNA. There are two types of DNA alkylating agents, monofunctional and bifunctional agents. Monofunctional alkylating agents mainly damage DNA by forming methylated adducts, whereas the damage induced by bifunctional alkylating agents includes monoadducts, intrastrand crosslinks and interstrand crossli...

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confidence: 99%

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Sanjiv

Suman

et al. 2011

Intl Journal of Cancer

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“…Certain amsacrine analogues have been found to be potent against the human breast carcinoma T-47D cell line and showed activity in phase II clinical studies on breast cancer (17,18). In spite of these successes, continuous efforts are made to develop novel 9-aminoacridine analogues with enhanced activity against breast cancer in pre-clinical studies (13,14,(19)(20)(21). A previous st udy by our group showed that CK0402 possesses activity against a broad spectrum of cancer types, including a panel of established human breast cancer cell lines (15).…”

Section: Discussionmentioning

confidence: 99%

CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells

Sun

Chen

Kwon

et al. 2015

Molecular Medicine Reports

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Abstract. 3-({4-[4-(Acridin-9-ylamino)phenylthio]phenyl} (3-hydroxypropyl)amino)propan-1-ol (CK0403) is a sulfur-containing 9-anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino) ethan-1-ol (CK0402) and amsacrine in the inhibition of the topoisomerase II-catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR-3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF-7, MDA-MB-231, BT474 and SKBR-3, as well as in the non-cancerous MCF-10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF-7. SKBR-3 and MDA-MB-231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR-3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR-3 cells revealed that, similarly to CK0402, CK0403 induced G 2 /M-phase arrest with a decreased S-and G 0 /G 1 -phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR-3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK04 02 aga inst est rogen receptor-negative a nd HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.

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“…Recently, a series of bi-functional anticancer chimeras, molecules capable of sequential DNA intercalation followed by DNA alkylation, was reported in the literature [14]. These bi-functional agents ultimately express their cytotoxic and antitumor effects by covalently binding one strand or cross-linking cellular DNA.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

et al. 2015

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Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward nonmalignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies. Graphical Abstract Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.Electronic supplementary material The online version of this article (

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Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage

Cited by 58 publications

References 24 publications

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells

Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

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