Antitumor agents alkylating

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

The Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course of synthesis of analogs of the antitumor agent camptothecin. 

The rationale for the cyclopent[Z>]indole design discussed above was that the quinone methide would build up in solution and intercalate/alkylate DNA. Enriched 13C-NMR studies indicate that the quinone methide builds up in solution and persists for hours, even under aerobic conditions (Fig. 7.21). In contrast, the quinone methide species formed by known antitumor agents (mitomycin C) are short lived and highly reactive. The spectrum shown in Fig. 7.21 also shows the N to O acyl transfer product that we isolated and identified. However, we could not determine if the quinone methide structure actually has the acetyl group on the N or O centers. 

Tomasz, M. Palom, Y. The mitomycin bioreductive antitumor agents cross-linking and alkylation of DNA as the molecular basis of their activity. Pharmacol. Ther. 1997, 76, 73-87. 

Prakash, A. S. Denny, W. A. Gourdie, T. A. Valu, K. K. Woodgate, P. D. Wakelin, L. P. G. DNA-directed alkylating ligands as potential antitumor agents sequence specificity of alkylation by intercalating aniline mustards. Biochemistry 1990, 29, 9799-9807. 

The isolation of diazobenzo[fr ]fluorenes as stable antitumor natural products raises several questions about their mode of action. The inability to cleave DNA by diazotization of 9-aminofluorene may imply that if the diazo functionality is involved in the mode of interaction of kinamycins with DNA, its conversion to diazonium and the ensuing reduction may seem to be of negligible importance. An additional possibility, which will be discussed later, is that 9-diazofluorene may not be the ideal model for these natural products. In exploring DNA cleavage as a possible route to the kinamycins role as a stable antitumor agent, which may supplement their speculative and as yet unconfirmed role as alkylating molecules [67], this early model seemed to suggest that the well-established activation of diazonium may not be relevant. 

Although N-methyl-N-nitrosourea can induce cancer in human beings, its derivatives were found to be potent antitumor agents. l,3-Bis(2-chloroethyl)-l-nitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and l-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-l-nitrosourea (PCNU) l-(2-Choroethyl)-3-(4-methylcyclo-hexyl)-l-nitrosourea and l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea showed antitumor activity by alkylating with DNA [82-84]. N-Nitrosourea-based prodrugs designed to become activated by tumor-associated proteases were found to provide enhanced... 

The pH value in a solid tumor is typically 0.2-0.5 units lower than in normal tissues. Therefore it may be possible to design pH-depen-dent cell-selective antitumor agents. Some free radicals are known to damage biological targets and especially to cleave nucleic acids (233). Alkylcobalt(III) complexes such as 53 generate alkyl radicals via ho-... 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

These antitumor agents are compounds that form carbonium ions or other reactive electrophilic groups. Such compounds bind covalently to DNA, and either crosslink the two strands of the helix or otherwise interfere with replication or transcription. Since these processes are more prevalent in rapidly dividing malignant cells than in normal tissues, alkylating agents can control and in some cases even eliminate tumors. However, their selectivity is limited and they have many and serious side effects. 

Figure 23-10 Some illustrative antitumor agents (biological alkylating agents)...

The alkylation products are synthetically useful because simple subsequent transformations furnishes precursors of important natural products as illustrated in Scheme 8E.23. Simple oxidative cleavage of allylic phthalimide 45 generates protected (5)-2-aminopimelic acid, whose dipeptide derivatives have shown antibiotic activity. The esterification via deracemization protocol is not limited to the use of bulky pivalic acid. The alkylation with sterically less hindered propionic acid also occurs with high enantioselectivity to give allylic ester 116, which has been utilized as an intermediate towards the antitumor agent phyllanthocin and the insect sex excitant periplanone. Dihydroxylation of the enantiopure allylic sulfone gives diol 117 with complete diastereoselectivity. Upon further transformation, the structurally versatile y-hydroxy-a,(f-un-saturated sulfone 118 is readily obtained enantiomerically pure. 

The dual alkylation/S Ar cyclization of A 1,A z-bis(2,4-dimethoxybenzyl)ethane-l,2-diamine (bis-DMB-ethylene-diamine) with the chloromethyl pyrimidine 102 provided the fused ring diazepine 103, a transformation that could not be accomplished by simply using unprotected ethylenediamine (Scheme 56). The product is an intermediate toward the synthesis of potential folate-related antitumor agents that act as glycinamide ribonucleotide formyltrans-ferase inhibitors <2004HC0405>. 

N. Bodor and J. J. Kaminski, Soft drugs. 2. Soft alkylating compounds as potential antitumor agents, J. Med. Chem. 23 566 (1980). 

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