Imidazoles. I. Coupling Reactions of 5-Diazoimidazole-4-carboxamide<sup>1,2</sup>

Shealy, Y. Fulmer; Krauth, Charles A.; Montgomery, John A.

doi:10.1021/jo01053a060

Cited by 131 publications

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“…Triazenes [3,3-bis(2-chloro ethyl)-l-triazeno] imidazolecarboxamides 16 constitute a series of prodrugs synthesized in the 1960s (Shealy et al 1962;Shealy and Krauth 1966). They arose empirically out of the synthetic program at the U.S. National Cancer Institute for agents potentially useful in the inhibition of purine metabolism.…”

Section: Triazenes and Hydrazinesmentioning

confidence: 99%

DNA Damaging Drugs

Weber

2015

Molecular Therapies of Cancer

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The classical anti-cancer agents comprise cytotoxic compounds. Mostly, these drugs act by exerting DNA damage. In essence, there are two major response phenotypes available to a cell upon DNA damage, such as a chemotherapeutic drug action, -to arrest the cell cycle and repair the damage, -to initiate a pathway to apoptosis (programmed cell death).In either scenario, the uncontrolled growth of the tumor cells is curtailed. The major limitation of the cytotoxic anti-cancer drugs is the tumor non-specific action, and the suppression of all rapidly dividing cells 1 . Alkylating AgentsAlkylating agents 2 are electrophilic and bind covalently to electron-rich functional groups of various target molecules via first-order or second-order nucleophilic substitutions (nucleophiles are electron-rich molecules or ions, such as OH − , H 2 O, halogenides, alcohols, thiols and amines). The first order reactants include aromatic and aliphatic nitrogen and sulfur mustards. Second order reactants include ethylene 1 Because the desired drug actions (damage to rapidly proliferating cancer cells) and the adverse effects (damage to rapidly proliferating healthy cells) are identical in targets and mechanisms, they are not separable. 2 Alkyl designates a functional group (a "side chain") that consists solely of single-bonded carbon and hydrogen atoms. Alkylating anticancer agents attach alkyl groups to biomolecules. imines and epoxides, alkylmethane sulfonates of the busulfan (Myleran) type, and α-halogenated acids, ketones, and their derivatives.-For first-order reactions, the rate limiting step is the ionization of the alkylating agent to form a positively charged carbonium ion, which then rapidly reacts with water, or a negative center, or a nucleophilic center. Within DNA and RNA, the most reactive site is the N 7 position of guanine ( Fig. 2.1). In DNA, this is followed by N 3 of adenine, N 1 of adenine, N 1 of cytosine, and N 7 of adenine (Table 2.1). The rate limiting step of the reaction is the formation of positively charged cyclic immonium ions, whereas the rate of the reaction is essentially independent of the nature and concentration of the nucleophilic target being attacked. -For second order nucleophilic substitutions, both reactants interact to form a transition complex. No carbonium ion is formed. The rate of the reaction depends on both concentrations, with bond strengths, electron affinity, and accessibility of both reagents being important (Knock 1967).Alkylating agents exert cytotoxic effects by transferring alkyl groups to DNA, thereby damaging the DNA and interfering with DNA transcription and cell division. This class of drugs mainly works by three distinct mechanisms:-The attachment of alkyl groups to DNA bases prevents DNA synthesis and RNA transcription, and it results in the DNA being fragmented by repair enzymes in a process to replace the altered bases. -The two arms of mustard drugs can cross-link DNA strands. In this process, two bases are linked together. Bridges can be formed within a single molecule of...

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Section: Triazenes and Hydrazinesmentioning

confidence: 99%

DNA Damaging Drugs

Weber

2015

Molecular Therapies of Cancer

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“…After removing the solvent under reduced pressure, the crude product was washed with petroleum etherdiethyl ether (50:50, v/v, 3×10 mL) and dried under reduced pressure to yield the product as a pale pink solid in 53% yield (0.128 g, 17). [25]. Solutions of 5-amino-1H-imidazole-4-carboxamide (0.2 M) in a mixture of aqueous HCl (0.6 M) and acetonitrile (3.5:6.5, v/v), HCl (0.6 M in water), and isoamylnitrite (0.2 M in acetonitrile) were prepared.…”

Section: -((3-mentioning

confidence: 99%

Protected Diazonium Salts: A Continuous-Flow Preparation of Triazenes Including the Anticancer Compounds Dacarbazine and Mitozolomide

Schotten¹,

Aldmairi²,

Sagatov³

et al. 2016

J Flow Chem

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Herein, we report a continuous-flow process for the preparation of triazenes, whereby diazonium salts are generated and converted into their masked or protected triazene derivatives. Key to realizing the process, which is applicable to a wide range of substrates, is the identification of solvent and reagent parameters that avoid fouling and clogging in the tubing used in these studies. The process has also been applied to prepare the antineoplastic agents mitozolomide and dacarbazine. We also report isolation and differential scanning calorimetry (DSC) analysis of an anthranilic acidderived triazene whose related diazonium salt is a contact explosive. The data highlights improved stability but also suggests that an exothermic process does occur with an onset temperature of 118°C. Finally, an 18-hour continuous operation of the reaction procedure using high-performance liquid chromatography (HPLC) pumps is reported.

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“…The compound 4(5)-(3,3-dimethyltriazeno-1)imidazol-5(4)-carboxamide (XXIV, dacarbazine) was synthesized in 1962 [31]. It had high antitumor activity [32].…”

Section: Imidazole Derivatives and Their Antitumormentioning

confidence: 99%

Imidazole derivatives and their antitumor activity (review)

Iradyan

Arsenyan

et al. 2009

Pharm Chem J

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Bis(2-chloroethyl)amino derivatives of imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, and imidazolylpeptides are reviewed. Data are presented for active compounds, some of which have passed the preclinical testing stage. Structures under consideration are interesting with respect to both the search for new antitumor drugs and the synthesis of compounds with different biological properties.Key words: imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, imidazolylpeptides, bis(2-chloroethyl)amino derivatives, antitumor activity.Chemotherapy of tumors is one of the most important medical achievements of the 20th century. Chemotherapy of malignant neoplasms was identified as an independent area of oncology in the middle of the 1940s with the advent of alkylating agents.It is currently possible to treat patients with Burkitt's lymphoma, Hodgkin's disease, chorionepithelioma, germinogenic ovarian diseases, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, breast and prostate cancer, and certain acute forms of leukemia and lymphosarcoma. However, any treatment method is ineffective at advanced stages of the disease in all instances.The ability to treat cancers with derivatives of bis(2-chloroethyl)amine was discovered serendipitously. The doctor on-board the transport ship John Harvey that was carrying mustard gas (1943) noticed the toxic effect of this compound on the blood of sailors. These and other observations signaled the beginning of studies on the effect of mustard gas and its derivatives on experimental and human tumors. Mustard gas itself is highly toxic and is not used in medical practice. A methyl analog of mustard gas, embichin, which was also one of the first antitumor preparations, was proposed in 1946 as a therapeutic. Searches in the next 20 -30 years in this direction discovered derivatives of bis(2-chloroethyl)-amine with aromatics such as novembichin, chlorambucil, paphencyl; with amino-acids, sarcolysine, asaline, lofenal; with hemi-alcohols, degranol; with phosphorylated amines, cyclophosphane; and with nitrogen-containing heterocycles, dopan and fluorodopan.A distinguishing feature of these preparations is the rather effective action on malignant systemic diseases of blood and hematopoietic organs.The presence of imidazole derivatives in man and their involvement in metabolism has drawn the attention of researchers. For example, a key compound in the biosynthesis of natural purine components of RNA and DNA is the ribotide 4(5)-aminoimidazol-5(4)-carboxamide [1,2]. Involvement of 4,5-aminoimidazolcarboxamide in metabolic processes can be used to synthesize its antimetabolites that can inhibit biosynthesis after biotransformations and thereby suppress tumor growth.The biological activity of bis(2-chloroethyl)amines is due to their interaction with carboxylic, sulfhydryl, and amino groups of proteins. They react with nucleic acids at the phosphoric-acid hydroxyls and DNA guanine at the 7-nitrogen atom [3].A characteristic of 2...

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Imidazoles. I. Coupling Reactions of 5-Diazoimidazole-4-carboxamide^1,2

Cited by 131 publications

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DNA Damaging Drugs

DNA Damaging Drugs

Protected Diazonium Salts: A Continuous-Flow Preparation of Triazenes Including the Anticancer Compounds Dacarbazine and Mitozolomide

Imidazole derivatives and their antitumor activity (review)

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Imidazoles. I. Coupling Reactions of 5-Diazoimidazole-4-carboxamide1,2

Cited by 131 publications

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DNA Damaging Drugs

DNA Damaging Drugs

Protected Diazonium Salts: A Continuous-Flow Preparation of Triazenes Including the Anticancer Compounds Dacarbazine and Mitozolomide

Imidazole derivatives and their antitumor activity (review)

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Imidazoles. I. Coupling Reactions of 5-Diazoimidazole-4-carboxamide^1,2