Modulation of the reactivity of nitrogen mustards by metal complexation: approaches to modify their therapeutic properties

Abstract

Metal complexation of nitrogen mustards shows promise with an ability to control the mustards’ reactivity, perform selective hypoxia activation, overcome resistance, and control GSH deactivation.

Removal of anthracycline cytostatics from aquatic environment: Comparison of nanocrystalline titanium dioxide and decontamination agents

“…This hypothesis was made on the basis of knowledge about the decomposition of mustard poisoning substances using nanoparticles of titanium oxides [32]. Cytostatics of the oxazophosphine family are derived from nitrogen mustards and are subject to the same adsorption and degradation phenomena [55]. These mechanisms appear to be useful for other classes of cytostatics, such as anthracycline antibiotics.…”

Oxamusplatin: a cytotoxic Pt(ii) complex of a nitrogen mustard with resistance to thiol based sequestration displays enhanced selectivity towards cancer

“…3 The nitrogen mustards are among the first chemotherapeutic agents against cancer, used in chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphoma, Hodgkin's disease, breast, ovarian and testicular cancer. 4,5 However, CDDP or nitrogen mustards both exhibit high toxicity to normal cells leading to severe side effects. 6 Attachment of various functionalities (viz.…”

“…glucose, folate, targeting peptides and vitamins to Pt-drugs or nitrogen mustards) increases efficacy towards therapeutic targets and minimises systemic toxicity. 4,[7][8][9][10][11][12] The structural properties of CDDP limits its use in the targeted delivery approach since after the dissociation of the other components, the active metal complex is still CDDP and hence would bear its drawbacks. Hence, the major disadvantages associated with CDDP are (i) the high systemic toxicity due to non-selectivity and ease of reactivity (ii) easy sequestration by copper transporter ATPases or other thiol donor molecules (viz.…”

“…[32][33][34][35] It has been shown that the reactivity of the nitrogen mustards can be controlled by coordinating the lone pair of the nitrogen with a metal ion. 4 In some cases, there may be total loss of activity, nevertheless, it is an important methodology to control the reactivity of nitrogen mustard which might otherwise lead to high systemic toxicity. In this regard, our earlier works show that incorporation of the nitrogen mustard ligand bis(2-chloroethyl)pyridylmethylamine provides higher steric hindrance and improves the stability of a dichlorido-Pt(II) complex.…”

“…In addition to the above, the already known advantages of the kinetic inertness of carboplatin and oxaliplatin led us to improve our design to circumvent sequestration pathways as well as lower the normal cell toxicity. 4,[11][12][13][14] Thus, incorporation of a chelating leaving group (viz. oxalate, cyclobutane-1,1-dicarboxylate) should make the complexes kinetically more inert towards deactivation by thiols.…”