Mercaptopurine derivatives

Chemical Class 6-Mercaptopurine derivative purine analog... 

A one-pot procedure for the transformation of 6-thiopurine nucleosides to 6-aminopurines was developed using DMDO as the oxidant in the presence of a stoichiometric amount of various amines <1996T6759>. For example, 6-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)purine was readily converted to the 6-alkylamino derivatives (6-amino, 75% yield 6-methylamino, 55% yield). Similarly, A -6-acetyl-8-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine was converted to A -6-acetyl-8-methylamino-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine (DMDO, methylamine, CH2CI2, 25 °C, 83% yield). Less nucleophilic 2-mercaptopurine derivatives did not undergo the displacement reaction, however, and only the products of dithiane formation and desulfurization were isolated. 

Mercaptopurine probably exists in a thione form (e.g., 167) since its ultraviolet spectrum is different from that of 2-(methylthio)pur-ine. Purine-2-thione and its 6-amino derivative were assigned thione structures on the basis of their infrared spectra.8-Mercapto-9-methyl- and b-mercapto-T-methjd-purine exist at least partially in thione forms, presumably 168 and 169, respectively, since their in-... 

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

Maintenance of remission of Crohn s disease may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

The effect of 6-mercaptopurine on the incorporation of a number of C-labelled compounds into soluble purine nucleotides and into RNA and DNA has been studied in leukemia L1210, Ehrlich ascites carcinoma, and solid sarcoma 180. At a level of 6-mercaptopurine that markedly inhibited the incorporation of formate and glycine, the utilization of adenine or 2-aminoadenine was not affected. There was no inhibition of the incorporation of 5(or 4)-aminoimidazole-4(5)-carboxamide (AIC) into adenine derivatives and no marked or consistent inhibition of its incorporation into guanine derivatives. The conversion of AIC to purines in ascites cells was not inhibited at levels of 6-mercaptopurine 8-20 times those that produced 50 per cent or greater inhibition of de novo synthesis [292]. Furthermore, AIC reverses the inhibition of growth of S180 cells (AH/5) in culture by 6-mercaptopurine [293]. These results suggest that in all these systems, in vitro and in vivo, the principal site at which 6-mercaptopurine inhibits nucleic acid biosynthesis is prior to the formation of AIC, and that the interconversion of purine ribonucleotides (see below) is not the primary site of action [292]. Presumably, this early step is the conversion of PRPP to 5-phosphoribosylamine inhibited allosterically by 6-mercaptopurine ribonucleotide (feedback inhibition is not observed in cells that cannot convert 6-mercaptopurine to its ribonucleotide [244]. 

A number of thiopurines (thioguanine, 6-mercaptopurine, 6-(methylthio) purine, azathioprine (6[( l-methyl-4-nitro-5-imidazolyl)thio] purine) [12],and other derivatives of 6-mercaptopurine [377]) have all been used to successfully prolong homografts, and azathioprine (Imuran) appears to be superior in its action [268]. 

Certain derivatives of 6-mercaptopurine, such as 6-(methylthio)purine, 6-mercaptopurine-3-oxide [448a], and 6-mercaptopurine ribonucleoside and its acylated derivatives apparently owe their activity to their in vivo conversion to 6-mercaptopurine [11,13]. It would appear, however, that the 9-alkyl derivatives of 6-mercaptopurine, and its arabinosyl and xylosyl derivatives, are not metabolized-except in the case of the 9-alkyI derivatives, to a limited extent to their 5-glucuronides—and that their mechanism of action is quite different from that of 6-mercaptopurine. 

Early attempts to inhibit H.Ep.-2 cells resistant to 6-mercaptopurine [464J resulted in the finding that a number of 9-alkyl derivatives of 6-mercaptopurine were highly active in this test system. 9-Alkylhypoxanthines and adenines were less effective [465]. 

P/7armaco/ogy Azathioprine, an imidazoyl derivative of 6-mercaptopurine (6-MP), has many biological effects similar to those of the parent compound. 

CV investigations of 6-mercaptopurine and 8-mercaptoquinoline SAMs on pc-Au electrodes have been presented by Madueno et al. [186] and He etal. [187], respectively. Several model electrode reactions involving various redox probes were studied using such modified electrodes. Baunach and Kolb etal. [188] have deposited copper on disordered benzyl mercaptan film on Au(lll) surfaces. They have also studied the behavior of benzyl mercaptan SAM on Au(lll) in H2SO4 solution using CV and STM. Structural and electrical properties of SAMs based on tetrathiafulvalene derivatives on Au(lll) were investigated. These mono-layers were disordered, or at least loosely... 

Nucleotides and nucleosides have emerged as important molecules in medicinal chemistry. In the 1950s, Elion and Hitchings discovered that 6-mercaptopurine had antitumor properties. This pioneering discovery opened the door for many subsequent studies of nucleotide derivatives as therapeutics. Acyclovir (8.3), a nucleoside that lacks two carbon atoms of its ribose ring, is effective in the treatment of herpes infections. Allopurinol, a purine derivative, is useful in the treatment of gout. 

Reaction of 6-mercaptopurine with sodium bicarbonate and epichlorohydrin in ethanol for 7 days at room temperature gave the expected chlorohydrin derivative. Unexpectedly, when this was treated with two equivalents of sodium methoxide in methanol at room temperature for 24 hours it did not give either epoxide or methoxy containing derivatives. Instead, the product, obtained in 32% yield, was the substituted thietane 1. 

Azathioprine is a derivative of mercaptopurine and, like the parent drug, functions as a structural analog or antimetabolite (Chapter 55 Cancer Chemotherapy). Although its action is presumably mediated by conversion to mercaptopurine, it has been more widely used than mercaptopurine for immunosuppression in humans. These agents represent prototypes of the antimetabolite group of cytotoxic immunosuppressive drugs, and many other agents that kill proliferative cells appear to work at a similar level in the immune response. 

C. Thapliyal and J. L. Maddocks, Separation of thiols as phenyl mercury derivatives by thin-layer chromatography I. Azathio-prine and 5-mercaptopurine metabolites, J. Chromatogr., 160 239 (1978). 

In the related mercapto derivatives this corresponds to the thione-tliiol tautomerism, illustrated by structures 10 and 11 for the important antitumor agent 6-mercaptopurine. 

Drugs used in cancer chemotherapy are cytotoxic drugs, hormones, plant derivatives, radioactive isotopes, and miscellaneous agents (e.g., procarbazine, hydroxyurea, mitotane). The plant-based drugs vincristine, vinblastine, vinorel-bine, etoposide, and campothecins. Radioactive isotopes, such as 131 iodine (131 I), are used in the treatment of thyroid tumors. Cytotoxic drugs (e.g., cis-platin, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate are used for the treatment of cancer. 

Mercaptopurine (6-thioxo-l,6-dihydropurine) was one of the first purine derivatives to find application in the treatment of leukaemia, especially in children. The drug inhibits the biosynthesis of purine nucleosides, including the conversion of IMP to AMP (54M140905, B-66MI40900). The 5-imidazolyl derivative (384), azathiopurine or Imvran, has also been of value as a suppressor of the immune response. 

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