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

Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential anticancer alkylating agents. These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell line...

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Published in:	Journal of medicinal chemistry 2000-04, Vol.43 (8), p.1484-1488
Main Authors:	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
Format:	Article
Language:	English
Subjects:	Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Carbamates - chemical synthesis Carbamates - chemistry Carbamates - pharmacology Drug Screening Assays, Antitumor General aspects Humans Medical sciences Mice Neoplasm Transplantation Nitroso Compounds - chemical synthesis Nitroso Compounds - chemistry Nitroso Compounds - pharmacology Pharmacology. Drug treatments Structure-Activity Relationship Tumor Cells, Cultured
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creator	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
description	Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential anticancer alkylating agents. These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD-1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents showed good activity with IC50 values in the range of 1−10 μg/mL against at least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso-4-acetoxybenzyl ester (3), was selected for further study in vivo against intraperitoneally implanted P388 murine leukemia. In addition to the aforementioned compound, both carbamic acid, (2-chloroethyl)nitroso-4-nitrobenzyl ester (9) and carbamic acid, (2-chloroethyl)nitroso-2,3,4,6-tetra-O-acetyl-1-α,β-d-glucopyranose ester (24) were evaluated against subcutaneously implanted M5076 murine sarcoma in mice. None of these compounds were active in vivo.
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These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD-1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents showed good activity with IC50 values in the range of 1−10 μg/mL against at least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso-4-acetoxybenzyl ester (3), was selected for further study in vivo against intraperitoneally implanted P388 murine leukemia. In addition to the aforementioned compound, both carbamic acid, (2-chloroethyl)nitroso-4-nitrobenzyl ester (9) and carbamic acid, (2-chloroethyl)nitroso-2,3,4,6-tetra-O-acetyl-1-α,β-d-glucopyranose ester (24) were evaluated against subcutaneously implanted M5076 murine sarcoma in mice. None of these compounds were active in vivo.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm990417j</identifier><identifier>PMID: 10780904</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Carbamates - chemical synthesis ; Carbamates - chemistry ; Carbamates - pharmacology ; Drug Screening Assays, Antitumor ; General aspects ; Humans ; Medical sciences ; Mice ; Neoplasm Transplantation ; Nitroso Compounds - chemical synthesis ; Nitroso Compounds - chemistry ; Nitroso Compounds - pharmacology ; Pharmacology. 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Med. Chem</addtitle><description>Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential anticancer alkylating agents. These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD-1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents showed good activity with IC50 values in the range of 1−10 μg/mL against at least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso-4-acetoxybenzyl ester (3), was selected for further study in vivo against intraperitoneally implanted P388 murine leukemia. In addition to the aforementioned compound, both carbamic acid, (2-chloroethyl)nitroso-4-nitrobenzyl ester (9) and carbamic acid, (2-chloroethyl)nitroso-2,3,4,6-tetra-O-acetyl-1-α,β-d-glucopyranose ester (24) were evaluated against subcutaneously implanted M5076 murine sarcoma in mice. None of these compounds were active in vivo.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Carbamates - chemical synthesis</subject><subject>Carbamates - chemistry</subject><subject>Carbamates - pharmacology</subject><subject>Drug Screening Assays, Antitumor</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Neoplasm Transplantation</subject><subject>Nitroso Compounds - chemical synthesis</subject><subject>Nitroso Compounds - chemistry</subject><subject>Nitroso Compounds - pharmacology</subject><subject>Pharmacology. 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Med. Chem</addtitle><date>2000-04-20</date><risdate>2000</risdate><volume>43</volume><issue>8</issue><spage>1484</spage><epage>1488</epage><pages>1484-1488</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential anticancer alkylating agents. These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD-1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents showed good activity with IC50 values in the range of 1−10 μg/mL against at least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso-4-acetoxybenzyl ester (3), was selected for further study in vivo against intraperitoneally implanted P388 murine leukemia. 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source	American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
subjects	Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Carbamates - chemical synthesis Carbamates - chemistry Carbamates - pharmacology Drug Screening Assays, Antitumor General aspects Humans Medical sciences Mice Neoplasm Transplantation Nitroso Compounds - chemical synthesis Nitroso Compounds - chemistry Nitroso Compounds - pharmacology Pharmacology. Drug treatments Structure-Activity Relationship Tumor Cells, Cultured
title	Synthesis and Evaluation of Several New (2-Chloroethyl)nitrosocarbamates as Potential Anticancer Agents
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