Synthesis and Evaluation of Several New (2-Chloroethyl)nitrosocarbamates as Potential Anticancer Agents

Reynolds, Robert C.; Tiwari, Anita; Harwell, Joyce E.; Gordon, Deborah G.; Garrett, Beverly D.; Gilbert, Karen S.; Schmid, Steven M.; Waud, William R.; Struck, Robert F.

doi:10.1021/jm990417j

Cited by 23 publications

(15 citation statements)

References 16 publications

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“…in the lung, breast and prostate) may show considerable benefit from chemotherapy or hormonal manipulation. Cancer suspect agents like epoxides, aziridines and N-nitroso compounds (Reynolds et al 2000) served as a starting point for the development of anti-cancer agents in the past. The furanone lead structure of our study and selected anti-cancer agents (Ayuko & Lattmann 1999) are outlined in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents

Lattmann

Ayuko

Kinchinaton

et al. 2003

Journal of Pharmacy and Pharmacology

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Bis-cyclic butenolides, 5-arylated 2(5H)-furanones 6a - c, 7a, b and the 3(2H)-pyridazones 9a - d were prepared by using the aldehyde form of muco halogen acids in electrophilic substitution reactions and in an aldol-like condensation reaction. The cytotoxicity of these simple and bis-cyclic butenolides have been evaluated in tissue culture studies on MAC 13 and MAC 16 murine colon cancer cell lines. The butyl furanone 3 displayed the highest cytotoxicity of 3 microM, as one selected example of a series of dichlorinated pseudoesters. The 5-arylated 2(5H)-furanones 6 and 7 did not show a structure-activity relationship (SAR) depending on the substitution pattern of the aromatic system. An IC50 (concentration inhibiting growth by 50%) was found within a range of 30-50 and 40-50 microM for the MAC 13 and MAC 16 cell lines, respectively. The pyridazine series 9 showed a maximum in-vitro activity for the p-methoxydrivative 9b, having an IC50 of 17 in MAC 13 and 11 microM in MAC 16 cell lines. Selected examples of each series and further novel 2(5H)-furanones such as the hydrazone 5 and the hydantoin 8 have been screened in-vivo in mice and the data are presented. For the pyridazines 9a - d, the in-vitro cytotoxicity correlated with an in-vivo inhibition of tumour growth. The ring expansion of the 5-membered 2(5H)-furanone ring system such as 6a into the 6-membered 3(2H)-pyridazone 9b led to an agent with improved antineoplastic properties. On the resistant MAC 16 cell line the pyridazone 9b displayed 52% tumour inhibition in mice at a dose of 50 mg kg(-1) compared with 27% for the 5-FU standard.

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Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents

Lattmann

Ayuko

Kinchinaton

et al. 2003

Journal of Pharmacy and Pharmacology

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“…Compound 29 was also effective in vivo in mice. On the other hand, the related (2-chloroethyl)nitroso carbamate 30 [69] demonstrated no in vivo activity.…”

Section: Nitroaromaticsmentioning

confidence: 96%

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

Groot¹,

Damen²,

Scheeren

2001

CMC

114

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In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.

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“…Pyrimidine ring is the building unit of DNA and RNA, due to which pyrimidine derivatives exhibit diverse pharmacological activities such as anticancer [2][3][4][5][6][7][8][9][10], antiviral [11][12][13] especially anti-HIV [14][15][16], antimalarial [17][18][19], antimicrobial [20,21] and anti-inflammatory [22,23]. They also exhibit activity against gonadotropin releasing hormone receptors and display herbicidal potential by inhibiting acetohydroxyacid synthase, a key enzyme in the biosynthesis of branched-chain amino acids [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…Diamino-6,7-dihydro-5H-pyrolo[2,3]pyrimidine derivative.in vitro endothelial capillary formation assay was also performed with Human umbilical vein endothelial cells (HU-VEC) and compound (124) inhibited Fibrinoblast Growth Factor induced capillary formation in dose dependent manner.Xiao et al filed a patent on 2,4'-diamino-6,7-dihydro-5H-pyrolo[2,3]pyrimidine derivatives as Focal Adhesion Kinases (FAK/Pyk2) inhibitors for treatment of FAK/Pyk2 mediated proliferative disease or disorder. Most of the synthesized compounds were potent and having IC 50 value less than 20nM against FAK and Pyk2.…”

mentioning

confidence: 99%

Anti-Cancer Pyrimidines in Diverse Scaffolds: A Review of Patent Literature

Kaur

Sharma

et al. 2014

PRA

104

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Pyrimidine ring is the building unit of DNA and RNA and thus pyrimidine based chemical architectures exhibit diverse pharmacological activities. Among the reported medicinal attributes of pyrimidines, anticancer activity is the most extensively reported. The anticancer potential of pyrimidines in fused scaffolds has also been evidenced through number of research article and patent literature. The pyrimidines based scaffolds have exerted their cell killing effects through varied mechanisms which indicate their potential to interact with diverse enzymes/ targets/receptors. This review article strictly focuses on the patent literature from 2009 onwards. The structure of the potent compounds, their IC50 values, models/assays used for the anticancer evaluation and the enzymes/ receptors/ targets involved have been presented in this compilation. Significant number of patents i.e. 59 have been published on pyrimidine based anticancer agents from 2009-2014 (from 2009 through the present date) which clearly indicate that this heterocycle is an area of focus at present for researchers all over the globe. Moreover, out of the 59 patents published during this period, 32 have been published from 2012 onwards which further highlights the present interest of the researcher towards pyrimidine based anticancer agents. The promising activity displayed by these pyrimidine based scaffolds clearly places them in forefront as potential future drug candidates. The present compilation can be extremely beneficial for the medicinal chemists working on design and synthesis of anticancer drugs.

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Synthesis and Evaluation of Several New (2-Chloroethyl)nitrosocarbamates as Potential Anticancer Agents

Cited by 23 publications

References 16 publications

Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents

Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

Anti-Cancer Pyrimidines in Diverse Scaffolds: A Review of Patent Literature

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