Mechanism and reactivity of chlorambucil and chlorambucil–spermidine conjugate

Abstract

The mechanism and kinetics of hydrolysis of chlorambucil and chlorambucil-spennidine conjugate in aqueous buffered solutions have been compared. In the absence of added chloride ion the reactions are shown to be first-order in the nitrogen mustard and independent of the nucleophile concentration. In the presence of high concentrations of sodium chloride the reaction is reversible and is subject to a significant common-ion effect. The rates of hydrolysis of both compounds are independent of pH in the range 8 to 3.5, and both rates begin to drop rapidly below pH 3.5 which corresponds to the pK,s of the aryl amine groups. The relative rates of alkylation of a range of nucleophiles by chlorambucil have been deduced from the isokinetic points, and have shown that the phosphate dianion, imidazole base and particularly thiolates are all capable of competing with water for the aziridinium ion at comparatively low concentrations. The rates of reaction of chlorambucil and the chlorambucil-spermidine conjugate have been shown to be sensitive to the medium, and, in particular, there is a large micellar inhibition of the hydrolysis of chlorambucil(60-fold reduction in rate) in the presence of hexadecyltrimethylammonium chloride that is not seen for the conjugate. These data are all accounted for in terms of a rate limiting formation of the aziridinium ion intermediate in each case. No evidence for any other mechanistic pathways was found.

Role of Thiocyanate Ion in Detoxification of the Anticancer Agent Chlorambucil

“…The increase in Cl -concentration from 0 to 0.5 M decreased the rate of hydrolysis of 1 in the absence of SCN -by a factor of 5.7. The observed rate retardation is somewhat larger than that reported by Chatterji et al (9) and Culls et al (10) in phosphatebuffered media. The difference arises, in all likelihood, from the reaction of 1 with phosphate dianion which partially cancels the effect of Cl -.…”

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

“…These conjugates have included DNA intercalating agents and alkylating agents such as chlorambucil, acridine and nitroimidazoles [6,[24][25][26][27][28], and also quinines [29], naphtoquinones [30] and topoisomerase I inhibitors such as camptothecin [31]. Overall, several of these conjugates demonstrated favourable in vitro pharmacological properties [32,33]. However, in vivo antitumor activity was described for only a few of them and appeared to be of a moderate level or not superior to that of the parent compound [27,28,33].…”

Liposomes Assembled from a Dual Drug‐tailed Phospholipid for Cancer Therapy

“…sPLA2)a nd then induced cell apoptosis via the accumulation of persistentD NA damage like the nitrogen mustards. [52] To our surprise, the liposomes exhibited higher cytotoxic effects against all of the cell lines than that observed with an equivalent dose of free DCTP andf ree chlorambucil. This is probably because the DCTP liposomes are stable before entering into cells and could release free drug and kill cancer cells effectively after entering, resulting in high cytotoxicity.B yc omparison, parts of free DCTP and free chlorambucil molecules might have degraded before entering into and killing the cancer cells due to their poor stability in PBS( pH 7.4) at 37 8Ca sm entioneda bove (Figure 3a).…”