Alkylating agent acrolein

The Jackson laboratory of the du Pont Company soon became interested in the catalytic power of hydrogen fluoride. The results of its work are recorded in three excellent papers. Using acrolein as the alkylating agent and hydrogen fluoride as the catalyst, peri syntheses have been performed (Calcott et al, 32), both those that are catalyzed by sulfuric acid and others that are not. By appropriate condensation, dehydration, and reduction, perylene was obtained from phenanthrene... 

Cyclophosphamide (Cytoxan) is the most versatile and useful of the nitrogen mustards. Preclinical testing showed it to have a favorable therapeutic index and to possess the broadest spectrum of antitumor activity of all alkylating agents. As with the other nitrogen mustards, cyclophosphamide administration results in the formation of cross-links within DNA due to a reaction of the two chloroethyl moieties of cyclophosphamide with adjacent nucleotide bases. Cyclophosphamide must be activated metabofically by microsomal enzymes of the cytochrome P450 system before ionization of the chloride atoms and formation of the cyclic ethylenimmonium ion can occur. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moiety derived from cyclophosphamide. 

Mechanism of action Cyclophosphamide [sye kloe FOSS fa mide] is the most commonly used alkylating agent. Both cyclophosphamide and ifosfamide [eye FOSS fa mide] are first biotransformed to hydroxylated intermediates by the cytochrome P-450 system (Figure 38.13). The hydroxylated intermediates undergo breakdown to form the active compounds, phospho-ramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. [Note The therapeutic effect of these drugs is independent of the level of activity of the cytochrome P-450 system.]... 

What are the biological consequences of the covalent modifications caused by alkylating agents One that we have already noted is the introduction of mutations opposite a modified base. Another one is the inhibition of DNA synthesis e.g., some of the acrolein adducts of guanine (Figure 13.8b) inhibit the incorporation of any base opposite to them, thus interfering with DNA s3uithesis and repair. Of note, many of these chemical adducts are removed by DNA repair enzymes only inefficiently or not at all the enzymes are apparently not accustomed to these peculiar types of modifications . 

Cyclophosphamide and ifosfamide are nitrogen mustard derivatives, and are widely used alkylating agents (Table 124—14). They are closely related in structure, clinical use, and toxicity. Neither agent is active in its parent form and must be activated by mixed hepatic oxidase enzymes. The active metabolite of cyclophosphamide is phosphoramide mustard. Another metabolite, 4-hydroxycyclophos-phamide is cytotoxic, but is not an alkylating agent. Ifosfamide is hepaticaUy activated to ifosfamide mustard. Acrolein, a metabolite of both cyclophosphamide and ifosfamide, has little antitumor activity, but is responsible for some of their toxicity. ... 

Alkylating agent nitrogen mustard derivative cross-links DNA-DNAor DNA-protein inhibits DNA synthesis activated by hepatic microsomal (CYP450) mixed function oxidases acrolein metabolite (no antitumor activity) associated with hemorrhagic cystitis... 

Cyclophosphamide Alkylating agent—attacks guanine N7—dysfunctional DNA Non-Hodgkin s, ovarian, breast CA, neuroblastoma BMS, mucositis, hemorrhagic cystitis (mesna, traps acrolein and is protective), hepatotoxicity (high dose)... 

Deprotonation of 379,381 and 383 can be accomplished with EtONa in ethanol, NaH in toluene or DMF, or with tetramethylguanidine in dichloromethane. Alkyl/benzyl bromides are usually employed as alkylation agents chlorides and iodides are less commonly used. In a few cases Mannich bases have been used ". Also, Michael additions using a,)3-unsaturated carbonyl compounds and esters are feasible, as documented with the synthesis of (7 /S)-[2- C]homoserine (from acrolein) and [2- C]- and glutamic acid (from... 

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