In the Search for New Anticancer Drugs, II¹ Antitumor Activity, Toxicity and Electron Spin Resonance of Spin Labeled Thio-TEPA Derivatives

Abstract

<jats:p>The spin labeled analog of Thio-Tepa, 1-oxyl-2,2,6,6-tetramethyl-4-piperidyl-N,N;N′,N′−bis (ethylene)−phosphorodiamidothioate (SL−O−TT), which contains a nitroxyl free radical linked by an oxygen bridge to phosphorus, has antitumor properties against P388 murine leukemia (T/C = 242) and a higher therapeutic ratio (5.15) than its parent compound, Thio-TEPA (2.75). The drug is less toxic to P388 cells in culture as judged by the <jats:sup>3</jats:sup>H-thymidine uptake. On the basis of electron spin resonance spectroscopy using L1210 cells incubated with SL−O−TT, it is concluded that the drug is bound to cells in culture in such a way as to restrict the motion of the nitroxyl label. A second spin labeled analog, 1-oxyl-2,2,6,6-tetramethyl-4-amino-piperidyl-N,N;N′,N′−bis (ethylene)−phosphorodiamidothioate (SL−NH−TT), containing a nitroxyl label linked by a nitrogen bridge to phosphorus, first synthesized by Russian workers, was prepared by an improved procedure in 95% yield. In vivo results indicate that this analog has about the same therapeutic value (2.73) as Thio-TEPA (2.75), and that higher doses of this compound are required than those for both the O-bridged analog and Thio-TEPA to achieve maximum T/C values.</jats:p>

In the search for new anticancer drugs. 9. Synthesis and anticancer activity of spin-labeled analogs of N,N:N',N':N",N"-tris(1,2-ethanediyl)phosphoric triamide and N,N:N',N':N",N"-tris(1,2-ethanediyl)phosphorothioic triamide

“…Compounds with a test/control (T/C) percentage greater than 125 or with a percent increase in life span (% ILS) (12) 7a 41 (7.5) 4b 96 (25) 7b34 (15) 5 44 (160) 833(160) 6 27 (20) 7c 16 (20) 14 81(30) 15 48 (30) 16a 29 (10) 16b 23 (10) ILS of 141 at a dose of 6 mg/kg was found to be the most active compound in this group, it is also probably the most toxic. 21 Promising activity was confirmed21 for compounds 4a ( % ILS = 103 at a dose of 12 mg/kg) and 4b (% ILS = 96 at a dose of 25 mg/kg). Although the -type compound 14 was reported to be inactive against the P388 lymphocytic leukemia,19 we found it to be considerable active with a % ILS of 81 at a dose of 30 mg/kg.…”

“…Distillation of the remaining oil (6.4 g) gave 5.4 g (50%) of lib: bp 82-84 °C (15 mm); n25D 1.4656. The compound was found to be pure by TLC, Rf 0.5 (neutral alumina; benzene/methylene chloride/methanol, 4:4:0.5, v/v) and GLC (injection 190 °C, column 185 °C, detector 215 °C); IR (neat) 3250 (NH) cm'1; MS, m/e 171 (M+ + 1,100), 140 (49), 83 (21);…”

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…The attachment of nitroxyl compounds to anticancer agents presents the attractive possibility of monitoring by EPR spectroscopy the interaction of the drugs with various cell biopolymers, such as, DNA, RNA, proteins, lipids, and carbohydrates, as well as their metabolism and tissue distribution. It was shown that while the nitroxyl moiety imparts a beneficial influence on the anticancer properties of a drug, ,− the nitroxyl group by itself has no anticancer activity, , is relatively nontoxic, is not carcinogenic or mutagenic, , exhibits no synergistic effect, and has little effect on the cell growth and the cell cycle kinetics . These facts can be explained , by assuming that the nitroxyl radical is a carrier group which facilitates the transport of the drug through the biological membranes to the cellular DNA.…”

“…Thus the covalent bonding of a nitroxyl group to anticancer agents could result in an increase in the therapeutic index, i.e. a broader range of safe doses …”

In the Search for New Anticancer Drugs, V+ Study of the Binding of Spin-Labeled Thio-TEPA to Cells

“…Recently, we reported [1] concerning the antitumor activity of two spin labeled analogs of the clinically used Thio-TEPA (1). Thus, SL-O-TT (2) and SL-NH-TT (3) [2] were evaluated, in accordance with the protocol [3], in vivo against lymphocytic P 388 murine leukemia.…”