Robert Stanley Mcelhinney

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.

Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O6-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O6-(4-bromothenyl)guanine (PaTrin-2, Patrin™, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC50 ∼6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg−1 i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and ∼60%, with extensive recovery by 24 h. PaTrin-2 (10 μM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D60=10 μM with PaTrin-2 vs 400 μM without). In MCF-7 xenografts, neither temozolomide (100 mg kg−1 day−1 for 5 days) nor PaTrin-2 (20 mg kg−1 day−1 for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2–temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P<0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2–temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

The reaction of the periodate-oxidation products of 1,4-anhydroerythritol and of some related pyrrolidine glycols with thiosemicarbazides

Abstract Simple analogues of the dialdehyde formed by periodate oxidation of benzyl β- L -arabinopyranoside have been prepared. Oxydiacetaldehyde may be condensed with one or two moles of substituted thiosemicarbazides, whereas N -aryliminodiacetaldehydes give only bis(thiosemicarbazones). The oxidation of N -arylpyrrolidine-3,4-diols with one equivalent of periodate is straightforward if electron-attracting aromatic substituents are present, but, otherwise, some cleavage of NC bonds in the pyrrolidine ring can be demonstrated. The crystalline hemialdal, 2,6-dihydroxy-4-phenylmorpholine, was isolated. The rates of conversion of some α-functionally-substituted thiosemicarbazones into glyoxal derivatives have been compared.

3-Heteraglutaraldehydes. Part II. Tetrahydrothiophen-3,4-diol 1,1-dioxides and the chemistry of their oxidation product, 3-thiaglutaraldehyde 3,3-dioxide, and its derivatives

Reproducible methods are described for the preparation of 3,4-epoxytetrahydrothiophen 1,1-dioxide and trans-tetrahydrothiophen-3,4-diol 1,1-dioxide by acid-catalysed reactions of 2,5-dihydrothiophen 1,1-dioxide with hydrogen peroxide. Earlier confusing accounts of the effect of acetic and formic acids have been clarified. The trans- as well as the more reactive cis-diol was oxidised by periodate to 2,2′-sulphonyldiacetaldehyde. In reaction with nitrogen-, sulphur-, or oxygen-containing nucleophiles, the dialdehyde formed crystalline linear derivatives and the only cyclic compounds readily obtained were 2-acetoxy-6-phenylthio-1,4-oxathian 4,4-dioxide and 1,4-dithian-2,6-diol 4,4-dioxide. 2,2′-Sulphonyldi(acetaldehyde oxime) was dehydrated to sulphonyldiacetonitrile, also prepared by oxidation of the known thiodiacetonitrile. An alternative approach to the dialdehyde by addition of sulphuryl chloride to ethyl vinyl ether was unsuccessful.

3-Heteraglutaraldehydes. Part III. The 1,2-dithian-4,5-diols and tetra-hydrothiophen-3,4-diols and their oxidation by periodate

Both isomers of the title diols have been prepared by improved methods. The diacetates of the dithiandiols were readily oxidised to stable, crystalline thiolsulphinates, and with difficulty to thiolsulphonates. Bisdisulphides were formed by reaction of a thiol with the thiolsulphinates. Tris(dimethylamino)phosphine abstracted sulphur from the trans-thiolsulphinate yielding a contracted ring (sulphoxide), whereas tributylphosphine regenerated disulphide by deoxygenation. The dithiandiols reacted readily with Chloramine-T; the trans-compound afforded two isomeric bicyclic sulphenate ester derivatives. Periodate oxidised the tetrahydrothiophendiols to either 3-thia-glutaraldehyde or its 3-oxide, and the dithiandiols to 3,4-dithia-adipaldehyde. The rates of oxidation were compared with those of other cyclic vicinal diols. A number of derivatives were prepared.