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Biomedical subjects

C Fairchild

Publications and source records attributed to C Fairchild.

At least 19 recordsLinked to original sources
PubMed2001

Synthesis of 7beta-sulfur analogues of paclitaxel utilizing a novel epimerization of the 7alpha-thiol group.

Paclitaxel analogues with a sulfur group at the 7beta position were required for SAR studies. Attempts to generate these compounds by displacing a 7alpha leaving group with sulfur nucleophiles were unsuccessful. Instead, these compounds were successfully prepared from a 7beta-thiol intermediate that was obtained by a base-catalyzed epimerization of the 7alpha-thiol derivative. The epimerization presumably proceeds through a thioaldehyde intermediate and exhibits the opposite stereochemical preference of its oxygen counterpart.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes.

Transition-state theory has led to the design of Immucillin-H (Imm-H), a picomolar inhibitor of purine nucleoside phosphorylase (PNP). In humans, PNP is the only route for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T cell-mediated immunosuppression. This study reports the biological effects and mechanism of action of Imm-H on malignant T cell lines and on normal activated human peripheral T cells. Imm-H inhibits the growth of malignant T cell leukemia lines with the induction of apoptosis. Imm-H also inhibits activated normal human T cells after antigenic stimulation in vitro. However, Imm-H did not inhibit malignant B cells, colon cancer cell lines, or normal human nonstimulated T cells, demonstrating the selective activity of Imm-H. The effects on leukemia cells were mediated by the cellular phosphorylation of deoxyguanosine and the accumulation of dGTP, an inhibitor of ribonucleotide diphosphate reductase. Cells were protected from the toxic effects of Imm-H when deoxyguanosine was absent or when deoxycytidine was present. Guanosine incorporation into nucleic acids was selectively blocked by Imm-H with no effect on guanine, adenine, adenosine, or deoxycytidine incorporation. Imm-H may have clinical potential for treatment of human T cell leukemia and lymphoma and for other diseases characterized by abnormal activation of T lymphocytes. The design of Imm-H from an enzymatic transition-state analysis exemplifies a powerful approach for developing high-affinity enzyme inhibitors with pharmacologic activity.

Apoptosis↗
PubMed2001

Preclinical antitumor activity of two novel taxanes.

PURPOSE: Two taxane analogs, BMS-184476 and -188797, were evaluated for their in vitro cytotoxicity and in vivo antitumor activity, and compared with paclitaxel and occasionally docetaxel (Taxotere). METHODS: Cytotoxicity was assessed in vitro using a panel of human tumor cell lines. Several different murine and human tumor models were used in vivo to evaluate the taxane analogs. RESULTS: Both compounds were found to have cytotoxic potency similar to paclitaxel and to partially overcome two different forms of paclitaxel resistance. BMS-184476 was found to be clearly superior to paclitaxel in three human xenograft tumor models: A2780 ovarian carcinoma; HCT/pk, a moderately paclitaxel-resistant colon carcinoma; and L2987 lung carcinoma. Additionally, in the clinically derived TAXOL-unresponsive ovarian carcinoma, HOC79, BMS-184476 performed slightly better than paclitaxel and Taxotere. BMS-184476 and paclitaxel were inactive in two murine model systems, M5076 sarcoma and the paclitaxel-resistant M109/txlr lung carcinoma. Against the parental M109 tumor, both BMS-184476 and paclitaxel performed comparably. BMS-184476 was never found to be inferior to paclitaxel. The other taxane analog, BMS-188797, displayed efficacy superior to paclitaxel in four in vivo tumor models: HOC79, HCT/ pk, M109, and L2987 carcinomas. Like paclitaxel and BMS-184476, BMS-188797 was inactive versus M5076 sarcoma. CONCLUSIONS: Two new taxane analogs were characterized as superior to paclitaxel or Taxotere in several in vivo tumor models. Both BMS-184476 and -188797 are currently in phase I or II clinical trials.

Animals↗
PubMed2000

Structure-activity relationships study at the 3'-N position of paclitaxel. Part 2: synthesis and biological evaluation of 3'-N-thiourea- and 3'-N-thiocarbamate-bearing paclitaxel analogues.

The syntheses and preliminary biological evaluation of 3'-N-thiocarbamate- and 3'-N-thiourea-bearing paclitaxel analogues, 4a-f and 5a-e, are described. 3'-N-thiocarbamates 4a-e were found to be more potent than paclitaxel in both the tubulin polymerization assay and the in vitro cytotoxicity assay. Several derivatives of this class such as 4c, 4d, and 4e also exhibited some in vivo activity.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Synthesis, structure proof, and biological activity of epothilone cyclopropanes.

[structure--see text] A semisynthetic route to epothilone cyclopropanes from epothilones A and B is described. Of significance, the deoxygenation of the 12, 13-epoxide to give the corresponding olefin was achieved with high efficiency. The title compounds (8, 9) were active in both tubulin polymerization and cytotoxicity assays, which is in direct contrast to a previously published report. These results provide further evidence that the role of the 12,13-epoxide of epothilones is largely conformational and argue against some of the current pharmacophore models.

Antineoplastic Agents↗
PubMed1999

Synthesis and biological evaluation of analogues of cryptolepine, an alkaloid isolated from the Suriname rainforest.

Bioassay-guided fractionation of an extract of a mixture of Microphilis guyanensis and Genipa americanacollected in the rainforest of Suriname yielded the known alkaloid cryptolepine (2) as the major active compound in a yeast bioassay for potential DNA-damaging agents; the same compound was later reisolated from M. guyanensis. The structure of cryptolepine was identified unambiguously by spectral data and by its total synthesis. Several cryptolepine derivatives (3-29, 32-41) were synthesized based on modifications of the C-2, N-5, N-10, and C-11 positions. Two cryptolepine dimers (30, 31) were also prepared. The structure modifications did not result in compounds with a higher potency than the parent compound cryptolepine in the yeast assay system, although some derivatives did show significant activity. Selected compounds (6, 7, 17, 22, 23, 26, and 27) were also tested for cytotoxicity in mammalian cell culture, and two compounds showed significant cytotoxic activity.

Alkaloids↗
PubMed1997

Studies in sugar chemistry. VII. Glucuronides of podophyllum derivatives.

The antitumor activities of several glucuronide methyl esters of podophyllum derivatives were tested in vitro against two human tumor cell lines and their drug resistant sublines. The most active compound studied was methyl (4'-carbobenzoxy-4'-demethyl-epipodophyllotoxin-D-glucopyranoside)uronat e 19. Compound 19 was as potent in a colon carcinoma model and was twice as potent in a lung carcinoma model as etoposide 6. In vivo, however, in a mouse leukemia P388 model, it had only marginal activity, with a maximum T/C% value of 125 at 37 mg/kg (iv).

Animals↗
PubMed1996

Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis.

The anticancer agent paclitaxel (Taxol) stabilizes tubulin polymerization resulting in arrest in mitosis and apoptotic cell death. Normal human fibroblasts depleted of functional p53 by SV40 T antigen or HPV-16 E6, and primary embryo fibroblasts from p53 null mice showed seven- to ninefold increased cytotoxicity by paclitaxel. Reduced levels of p53 correlated with increased G2/M phase arrest, micronucleation, and p53-independent paclitaxel-induced apoptosis. Surviving cells with intact p53 progressed through mitosis and transiently accumulated in the subsequent G1 phase, coincident with increased p53 and p21cip1,waf1 protein levels. These results are in contrast to studies linking p53 loss with resistance to DNA damaging anticancer agents.

Animals↗
PubMed1995

Synthesis and biological evaluation of novel C-4 aziridine-bearing paclitaxel (taxol) analogs.

Three novel C-4 aziridine-bearing paclitaxel analogs, 3-5, have been synthesized during the course of our continuing effort at C-4 modification. The key step in the synthesis is the aziridine ring formation at the C-4 position via an intramolecular Mitsunobu reaction. The syntheses and the biological evaluation of these C-4 aziridine-containing derivatives are herein discussed.

Aziridines↗
PubMed1993

Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum.

Eupenifeldin was isolated from cultures of Eupenicillium brefeldianum ATCC 74184 by extraction and crystallization. The compound was identified as a pentacyclic bistropolone on the basis of spectral data and its complete structure was established by single-crystal X-ray analysis. The compound is cytotoxic against the HCT-116 cell line and has in vivo antitumor activity in the P388 leukemia model.

Animals↗
PubMed1985

Alprazolam vs amitriptyline in depressions with reduced REM latencies.

This study was designed to compare the antidepressant effects of alprazolam, a triazolobenzodiazepine, with amitriptyline hydrochloride in a group of patients with nonpsychotic, major depressions diagnosed by Research Diagnostic Criteria. A mean rapid eye movement latency of less than 65 minutes was required to enter this study. Dexamethasone suppression tests were conducted before treatment. By strictly applied Research Diagnostic Criteria, 83.6% of the subjects were endogenous, and 34.7% were inpatients. A significantly greater percentage of alprazolam-treated patients responded within the first seven days of treatment. By the end of this six-week trial, alprazolam was associated with significant reductions in Hamilton, Beck, Covi, Raskin, and Carroll Rating scores (pretreatment to posttreatment). However, by the end of treatment the effects of amitriptyline exceeded those of alprazolam on both the Hamilton and Beck scales. These data indicate that alprazolam is not as effective as amitriptyline in major depressions with a shortened rapid eye movement latency.

Adolescent↗
PubMed1985

Free triiodothyronine (T3) and thyroxine (T4) in a group of unipolar depressed patients and normal subjects.

We examined levels of free triiodothyronine (fT3) and free thyroxine (fT4) in serum from a group of 32 patients with unipolar major depression and 46 normal control subjects using the Amerlex (Amersham, Arlington Heights, IL) RIA procedures for these hormones. Free T3 levels were significantly lower (p less than 0.004) in the depressed patients as a group (5.02 +/- 1.01 pmol/L, mean +/- SD) than in the normal control subjects (5.74 +/- 1.23 pmol/L). Free T3 levels were lower (p less than 0.01) in depressed men (5.25 +/- 1.43 pmol/L) when compared with male control subjects (6.46 +/- 1.01 pmol/L). Depressed women (4.78 +/- 0.60 pmol/L) also had lower T3 levels than did the female control subjects (5.09 +/- 1.06 pmol/L), but the difference was not statistically significant. Lower fT3 levels were also observed in melancholic depressed patients when compared with nonmelancholic depressed patients or when compared with normal control subjects. No differences in fT4 were observed between groups in this study.

Adolescent↗
PubMed1984

TRH-induced prolactin release is blunted in females with endogenous unipolar major depression.

Twenty-five women with unipolar primary major depressive disorder (20 endogenous, 5 nonendogenous) and 20 female control subjects were studied with the thyrotropin-releasing hormone stimulation test (TRH-ST). Prolactin (PRL) levels were measured before and after TRH administration for patients and control subjects. For patients, thyrotropin (thyroid-stimulating hormone; TSH) levels were measured from the same serum specimens as PRL levels, and the 1 mg dexamethasone suppression test (DST) was performed. Patients with endogenous depression (ED) had significantly lower maximal serum PRL levels (max PRL) following TRH, and a significantly reduced increase over basal serum PRL (delta max PRL) compared to normal controls (NC). Nonendogenous depressed (NED) patients did not differ significantly from the ED or NC groups on either of these measures. For the ED group, delta max PRL was inversely correlated with severity of depressive symptomatology. Basal PRL levels did not differentiate the depressed subgroups (ED, NED) from each other or from the NC group. Depressed patients with blunted delta max PRL values tended to have blunted delta max TSH values and vice versa. Almost all patients with blunting of either delta max PRL or delta max TSH were also DST nonsuppressors; conversely, only about half (7 of 12) of patients who were DST nonsuppressors had either blunted delta max PRL or delta max TSH. Patients with clinical diagnoses of melancholia or psychotic features were significantly more likely to have blunted delta max PRL values than patients without these diagnoses. A disturbance of central noradrenergic function could explain these findings.

Adult↗
PubMed1983

Psychobiological predictors of antidepressant drug response.

Forty-nine patients with major depression and a reduced (less than 65.0 minute) REM latency were treated in a randomized, double-blind study with either amitriptyline or alprazolam. Predictors of response were sought for the whole group and for each drug cell individually. A longer current episode and a higher Beck Depression Inventory to Hamilton Rating Scale ratio were predictive of a poorer response for the whole group and for the alprazolam group. A longer current episode was also predictive of a poor response to amitriptyline. These data suggest that (1) a longer current episode and (2) a greater level of self-reported compared to clinician-observed symptoms correlate with a poorer response to antidepressant medications.

Alprazolam↗