Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes

Kakadiya, Rajesh; Dong, Honglin; Lee, Pei‐Chih; Kapuriya, Naval; Zhang, Xiuguo; Chou, Ting‐Chao; Lee, Te‐Chang; Kapuriya, Kalpana; Shah, Anamik; Su, Tingwei

doi:10.1016/j.bmc.2009.06.018

Cited by 55 publications

(49 citation statements)

References 27 publications

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“…13 Furthermore, we found that several 3a-aza-cyclopenta[a]indene derivatives preferentially killed oral cancer cells in culture. 13 In our study, we further explored the anticancer activity of these newly synthesized compounds against oral cancer cells.…”

mentioning

confidence: 90%

“…1a) were synthesized as described previously. 13 These derivatives were used in our study because they selectively kill oral cancer cell lines compared to other cancer cell lines. 13 …”

Section: Experimental Compoundsmentioning

confidence: 99%

“…13,17 Apoptosis assay was performed by using an annexin V-FITC apoptosis detection kit (Calbiochem, La Jolla, CA) as described. 17 DNA damage assays DNA synthesis was assayed with a 5-bromo-2 0 -deoxyuridine (BrdU) labeling and detection kit from Roche.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

“…[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. 13 Furthermore, we found that several 3a-aza-cyclopenta[a]indene derivatives preferentially killed oral cancer cells in culture.…”

mentioning

confidence: 99%

“…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. 13 Furthermore, we found that several 3a-aza-cyclopenta[a]indene derivatives preferentially killed oral cancer cells in culture. 13 In our study, we further explored the anticancer activity of these newly synthesized compounds against oral cancer cells.…”

mentioning

confidence: 99%

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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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mentioning

confidence: 90%

“…1a) were synthesized as described previously. 13 These derivatives were used in our study because they selectively kill oral cancer cell lines compared to other cancer cell lines. 13 …”

Section: Experimental Compoundsmentioning

confidence: 99%

Section: Cytotoxicity Assaymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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Chemoselective Cascade Synthesis of N‐Fused Heterocycles via Silver(I) Triflate‐Catalyzed Friedel–Crafts/N‐C Bond Formation Sequence

et al. 2010

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An efficient cascade methodology toward chemoselective synthesis of N-fused heterocycles in-indole derivatives has been developed. This transformation proceeds via a silver(I) triflate-catalyzed consecutive FriedelCrafts reaction/N À C bond formation sequence between readily available propargyl alcohols and 3-substituted 1H-indoles. Not only is excellent chemoselectivity observed according to the substitution patterns of propargyl alcohols, but also the Lewis acid-catalyzed N À C bond formation process can be carried out under base-and ligand-free conditions.

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A Three‐Component Reaction of Aryldiazonium Tetrafluoroborates, Sulfur Dioxide, and 1‐(Prop‐2‐yn‐1‐yl)indoles under Catalyst‐Free Conditions

et al. 2018

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Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes

Cited by 55 publications

References 27 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

Chemoselective Cascade Synthesis of N‐Fused Heterocycles via Silver(I) Triflate‐Catalyzed Friedel–Crafts/N‐C Bond Formation Sequence

A Three‐Component Reaction of Aryldiazonium Tetrafluoroborates, Sulfur Dioxide, and 1‐(Prop‐2‐yn‐1‐yl)indoles under Catalyst‐Free Conditions

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