Functionalized heteroaromatic compounds and their deaminatively generated, ring-centered carbocation-counterion ion-pairs [electronic resource] : Synthesis and application as potential antitumor agents / Valentine Renique St Hilaire

St Hilaire, Valentine Renique
Bib ID
vtls000568992
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222 p.
電子版
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數位化論文典藏聯盟
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$a Functionalized heteroaromatic compounds and their deaminatively generated, ring-centered carbocation-counterion ion-pairs $h [electronic resource] : $b Synthesis and application as potential antitumor agents / $c Valentine Renique St Hilaire
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$a 222 p.
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$a Source: Dissertation Abstracts International, Volume: 61-03, Section: B, page: 1420.
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$a Adviser:  Emil H. White.
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$a Thesis (Ph.D.)--The Johns Hopkins University, 2000.
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$a <italic>Chapter 1.</italic> The protonation of heterocyclic diazotates (attachment adjacent to a ring nitrogen) produces highly reactive ring centered heterocyclic carbocations. Sodium 9-propyl-6-purine diazotate was synthesized and extensively studied to determine its suitability as an alkylating and potential antitumor agent. In particular, its acid decomposition was probed with a view to elucidating the relative significance of ionic versus free radical components. The major products were found to be derived <italic>via </italic> an ionic pathway providing a paradigm for the antitumor activity reported for sodium 2-pyrazine diazotate and supporting the intermediacy of a carbocation. The carbocation was reactive, as evidenced by its ability to alkylate benzene. Products (20%) of extraction of hydrogen and chlorine from chloroform, were also identified and are consistent with a free radical pathway. The results of cancer screening tests on the title compound, which show limited efficacy <italic>in vitro</italic> against a panel of 60 cell lines, are also presented.
520
$a <italic>Chapter 2.</italic> 2-Amino-6-chloropyrazine has been a synthetically useful intermediate in the synthesis of heterocycles having diverse properties e.g., antimycobacterial, analgesic, anticonvulsant, circulatory activity, antitubercular and antiviral, or as useful photographic couplers. The most widely used synthesis of 2-amino-6-chloropyrazine involves heating 2,6-dichloropyrazine with concentrated aqueous ammonia for 14 h at 135&ndash;140&deg;C in a sealed Carius tube. This section describes a higher yielding novel synthesis of 2-amino-6-chloropyrazine under reaction milder (certainly less hazardous) than those in sealed reaction vessels at elevated temperatures.
520
$a <italic>Chapter 3.</italic> Sodium pyrazine 2-diazotate is a compound with known antineoplastic properties, attributed to the highly reactive &alpha;-nitrogen stabilized 2-pyrazinyl carbocation. The polyamine 1,4-butanediamine (putrescine) also has antineoplastic properties; being able to generate powerful electrostatic interactions with the phosphate bases of DNA at physiological pH. Novel compounds utilizing the nitrosated 2-pyrazinamine ring and a polyamine side chain were synthesized and tested through the preclinical cancer screening tests of the National Cancer Institute. The rationale for the synthesis of these potentially novel antineoplastic agents as well as analysis of the preclinical tests are presented in this chapter.
520
$a <italic>Chapter 4.</italic> An apparatus was designed and successfully utilized for the measurement of the nitrogen gas produced in the reaction between heterocyclic diazotates and acetic acid. The molar quantity of gas evolved corresponded to the purity of the diazotate as confirmed by elemental analysis. The procedure provides a convenient, reproducible, and reliably accurate method for determination of the purity of these compounds (claimed to be difficult to purify).
520
$a <italic>Chapter 5.</italic> This chapter describes the successful combination of &alpha;-heteroarylamines, functionalized as triazenes, with a polyamine side chain in novel compounds with the antineoplastic properties of both a triazene and a polyamine. Acid decompositions of these triazenes were studied with a view to identifying the products and hence the mechanism of triazene decomposition. These results are interpreted in terms of the intermediacy of the inert-molecule-separated ion-pair. The syntheses of model 1-(aryl)-3-alkylamino triazenes as well as various approaches to 1(&alpha;-heteroaryl)-3,3-dialkyl triazenes are presented. Unimpressive data from the preclinical cancer screening tests on these novel compounds are discussed.
591
$a 數位化論文典藏聯盟 $b PQDT $c 中山大學(2001~2002)
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$a Chemistry, Organic.
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$a Chemistry, Pharmaceutical.
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$a White, Emil H., $e advisor
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$a THE JOHNS HOPKINS UNIVERSITY.
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<italic>Chapter 1.</italic> The protonation of heterocyclic diazotates (attachment adjacent to a ring nitrogen) produces highly reactive ring centered heterocyclic carbocations. Sodium 9-propyl-6-purine diazotate was synthesized and extensively studied to determine its suitability as an alkylating and potential antitumor agent. In particular, its acid decomposition was probed with a view to elucidating the relative significance of ionic versus free radical components. The major products were found to be derived <italic>via </italic> an ionic pathway providing a paradigm for the antitumor activity reported for sodium 2-pyrazine diazotate and supporting the intermediacy of a carbocation. The carbocation was reactive, as evidenced by its ability to alkylate benzene. Products (20%) of extraction of hydrogen and chlorine from chloroform, were also identified and are consistent with a free radical pathway. The results of cancer screening tests on the title compound, which show limited efficacy <italic>in vitro</italic> against a panel of 60 cell lines, are also presented.
<italic>Chapter 2.</italic> 2-Amino-6-chloropyrazine has been a synthetically useful intermediate in the synthesis of heterocycles having diverse properties e.g., antimycobacterial, analgesic, anticonvulsant, circulatory activity, antitubercular and antiviral, or as useful photographic couplers. The most widely used synthesis of 2-amino-6-chloropyrazine involves heating 2,6-dichloropyrazine with concentrated aqueous ammonia for 14 h at 135&ndash;140&deg;C in a sealed Carius tube. This section describes a higher yielding novel synthesis of 2-amino-6-chloropyrazine under reaction milder (certainly less hazardous) than those in sealed reaction vessels at elevated temperatures.
<italic>Chapter 3.</italic> Sodium pyrazine 2-diazotate is a compound with known antineoplastic properties, attributed to the highly reactive &alpha;-nitrogen stabilized 2-pyrazinyl carbocation. The polyamine 1,4-butanediamine (putrescine) also has antineoplastic properties; being able to generate powerful electrostatic interactions with the phosphate bases of DNA at physiological pH. Novel compounds utilizing the nitrosated 2-pyrazinamine ring and a polyamine side chain were synthesized and tested through the preclinical cancer screening tests of the National Cancer Institute. The rationale for the synthesis of these potentially novel antineoplastic agents as well as analysis of the preclinical tests are presented in this chapter.
<italic>Chapter 4.</italic> An apparatus was designed and successfully utilized for the measurement of the nitrogen gas produced in the reaction between heterocyclic diazotates and acetic acid. The molar quantity of gas evolved corresponded to the purity of the diazotate as confirmed by elemental analysis. The procedure provides a convenient, reproducible, and reliably accurate method for determination of the purity of these compounds (claimed to be difficult to purify).
<italic>Chapter 5.</italic> This chapter describes the successful combination of &alpha;-heteroarylamines, functionalized as triazenes, with a polyamine side chain in novel compounds with the antineoplastic properties of both a triazene and a polyamine. Acid decompositions of these triazenes were studied with a view to identifying the products and hence the mechanism of triazene decomposition. These results are interpreted in terms of the intermediacy of the inert-molecule-separated ion-pair. The syntheses of model 1-(aryl)-3-alkylamino triazenes as well as various approaches to 1(&alpha;-heteroaryl)-3,3-dialkyl triazenes are presented. Unimpressive data from the preclinical cancer screening tests on these novel compounds are discussed.
附註
Source: Dissertation Abstracts International, Volume: 61-03, Section: B, page: 1420.
Adviser: Emil H. White.
Thesis (Ph.D.)--The Johns Hopkins University, 2000.
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