Hydroxylation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) by rat liver microsomes

May, Hubert E.; Boose, Richard; Reed, Donald J.

doi:10.1016/0006-291x(74)90948-6

Cited by 57 publications

(19 citation statements)

References 9 publications

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“…Similar studies on the in vivo pharmacokinetics of CCNU in the presence or absence of MISO do not exist. However, since CCNU, unlike BCNU, undergoes ring hydroxylation by liver microsomal enzymes (May et at., 1974;Hilton & Walker, 1975;Wheeler et al, 1977) the possibility arises that the enhanced tumour response on the addition of MISO to CCNU treatment could be the result of altered CCNU metabolism in the presence of the sensitizer. The observations in the KHT sarcoma could be interpreted as supporting this view, since MISO, which undergoes oxidative demethylation, probably by liver microsomal mixed-function oxidases, enhances the cytotoxicity of CCNU, whereas Ro-05-9963 and SR-2508 are not metabolized in this manner (White et al, 1980) and are relatively ineffective (Table I).…”

Section: Resultsmentioning

confidence: 99%

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers

Siemann¹

1982

Br J Cancer

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Summary.-The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and nitroimidazole radiation sensitizers was evaluated in female C3H mice. Tumour response to single-agent or combination therapy was assessed in a tumour growth-delay assay. In the KHT sarcoma the simultaneous addition of misonidazole (MISO) was found to increase significantly the tumour growth delay resulting from CCNU treatment. The observed enhancement ratios (ER) increased with MISO dose, and ranged from 1x3 to 1-9 for sensitizer doses of 0-25-1l0 mg/g. The combination of CCNU and 1-0 or 0-5mg/g MISO in the RIF-1 tumour or the MT-1 tumour produced ERs of -2-0 and -15 respectively.In the KHT sarcoma a series of other nitroimidazole sensitizers, including Ro-05-9963, SR-2555, SR-2508 and metronidazole (METRO), were also evaluated at equimolar doses (5 mmol/kg) in combination with a 20mg/kg dose of CCNU. Unlike MISO, these compounds in general failed to enhance the CCNU cytotoxicity in this tumour model. However, SR-2508 did enhance the response of the RIF-1 tumour to large single doses of CCNU, though not as much as MISO.Normal-tissue toxicity was determined using peripheral white blood cell (WBC) counts 3 days after treatment. CCNU doses of 10-50 mg/kg given either alone or in simultaneous combination with 0 5 or 1-0 mg/g MISO were studied. WBC toxicity increased with CCNU dose, but the addition of MISO at either dose did not significantly enhance this normal-tissue toxicity.

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Section: Resultsmentioning

confidence: 99%

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers

Siemann¹

1982

Br J Cancer

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“…This material (3.64 g, 0.034 mol) was subjected to treatment with 1 M DC1-D20 as described above for the preparation of 8 and distilled to yield 6 (2.26 g, 627o): bp 153-155 °C (lit.36 for cyclohexanone 155 °C); mass spectrum m/e 108 (100, M+•), 107 (9). Cyclohexanone-3,3',4,4',5,5'-<f6 (7). Crude 6 (2.51 g, 0.023 mol) was heated under reflux with 1 M HC1 (300 mL) for 300 min and the product was isolated as described for 8 and distilled to give 7 (1.78 g, 747c): bp 152-155 °C; mass spectrum m/e 104 (100, M+•), 103 (9); NMR (CDC13) 1.60 (m, trace d5 analogue) and 2.32 (m, H-2,2', H-6,6').…”

Section: Methodsmentioning

confidence: 99%

“…Oxidation of cyclohexanol-d12 with chromic acid and treatment of the product with boiling 1 M HC1 completed exchange of the deuterium at C-2 and C-6 and gave cy- clohexanone-d6 (7). CCNU-d6 (3) derived therefrom via cyclohexylamine-d6 gave a mass spectrum with a peak intensity ratio of 100:10 for the ions at m/e 239 (M+• for CCNU-d6) and 238.…”

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confidence: 99%

Synthesis, metabolism, and antitumor activity of deuterated analogs of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea

Farmer¹,

Foster²,

Jarman³

et al. 1978

J. Med. Chem.

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Analogues of CCNU have been synthesized in which the cyclohexyl residue is partly (2,2',6,6'-d4, 3,3',4,4',5,5'-d6) or wholly deuterated (2,2',3,3',4,4',5,5',6,6'-d10) at positions susceptible to metabolic hydroxylation. Each deuterated analogue alone or in admixture with CCNU was incubated with rat liver microsomes, and the yields of each hydroxy derivative (trans-2-, -3-, and -4-OH, cts-3-and 4-OH) were measured by HPLC (individual derivatives) or by HPLC and mass spectrometry (mixtures). Increased retention times in HPLC due to deuterium substitution on the cyclohexyl ring were observed with the OH-CCNU isomers and nearly complete resolution of cis-and trons-4-OH-CCNU-d0 and -d9 was achieved. The total yield of OH derivatives from CCNU-d10 was 74% of that from CCNU, but the relative proportions of each OH-CCNU were very similar. CCNU-d4 yielded much less frans-2-0H-CCNU (0.2% of the total OH derivatives) than did CCNU (2.3%), whereas the yield (17%) of this isomer from CCNU-d6 was correspondingly greater. Thus, selective deuteration directs metabolism away from the sites of isotopic substitution (i.e., induces metabolic switching), although there is only a small isotope effect for the overall hydroxylation process.CCNU and its deuterated analogues had similar antitumor activities against the TLX-5 lymphoma in mice.l-(2-Chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) (1) is one of the most effective of the antitumor nitrosoureas against intraperitoneal and intracerebral leukemia L1210 in mice2 and is of use in the treatment of many human malignancies, particularly those of the brain3 where it is now often the drug of choice. CCNU decomposes rapidly in aqueous solution and among the many products are the reactive carbamylating agent, cyclohexyl isocyanate,4 and 2chloroethanol, the formation of which suggests the intermediacy of an alkylating moiety, possibly a 2-chloroethyl carbonium ion.5,6However, it is now considered likely that the antitumor effects of CCNU in vivo are due to its metabolites, as extensive and rapid hydroxylation of the cyclohexyl ring is mediated by microsomal enzymes in the liver.7"9 Seven isomers of ring-monohydroxylated derivatives of CCNU (OH-CCNU) are theoretically possible (1-OH-, cís-2--, trons-2--, cis-3--, trans-3--, as-4--, and frans-4-OH-CCNU). The formation of four (cis-3--, írans-3--, cts-4--, and írons-4-OH-CCNU) was established by HPLC and mass spectral and NMR characteristics.9,10 In previous work, a minor metabolite had HPLC and mass spectral properties similar to those of cts-2-OH-CCNU,9 but work presented in this paper has demonstrated that this metabolite is trans-2-OH-CCNU and that cfs-2-OH-CCNU is formed in even smaller amounts than the trans 2-isomer (Figure 1, Scheme I).Other workers have found 3-OHand 4-OH-CCNU isomers and írons-2-OH-CCNU but were unable to show the formation of the cis 2-isomer by liver microsomes from the rat11 and mouse.12 In the plasma of humans to whom CCNU had been administered, cts-4-OH-CCNU (the major

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“…The pyridine is not a helpful substitution to cyclohexyl because such hydrophilic radical can′t accommodate near the hydrophobic region of Phe226 in the active site. The 11‐hydroxyimidazoisoindole [Figure 8 (7)] exhibits rapid‐hepatic clearance due to the first‐pass metabolism of the cyclohexyl group [76] coupled with the high potency of the inhibitor against CYP 3 A4 (IC 50 =0.17 μM). They mitigated these PK problems by improving the polarity of the compound without compromising the biochemical potency.…”

Section: Discovery Of the Clinical Candidates Of Selective Hido1 Inhibitors And The Scheme Of Binding Inhibition Into The Enzyme Active Smentioning

confidence: 99%

Structural Basis of Selective Human Indoleamine‐2,3‐dioxygenase 1 (hIDO1) Inhibition

Kassab

Mowafy

2021

ChemMedChem

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hIDO1 is a heme−dioxygenase overexpressed in the tumor microenvironment and is implicated in the survival of cancer cells. Metabolism of tryptophan to N‐formyl−kynurenine by hIDO1 leads to immune suppression to result in cancer cell immune escape. In this article, we discuss the discovery of selective hIDO1 inhibitors for therapeutic intervention that have been promoted to clinical trials and for which crystallographic structural information is available for the respective inhibitor−enzyme complex. The structural insights are based on the complex crystal structures and the relative biological data profiles. The structural basis of selective hIDO1 inhibition, as discussed herein, opens new avenues to the discovery of novel inhibitors with improved activity profiles, selectivity, and distinct structure frameworks.

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Hydroxylation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) by rat liver microsomes

Cited by 57 publications

References 9 publications

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers

Synthesis, metabolism, and antitumor activity of deuterated analogs of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea

Structural Basis of Selective Human Indoleamine‐2,3‐dioxygenase 1 (hIDO1) Inhibition

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