Hydroxamic acids. V. The alkylation of O-alkylarylhydroxamic acids

1974 ◽  
Vol 27 (6) ◽  
pp. 1341 ◽  
Author(s):  
PM Beart ◽  
AD Ward
Keyword(s):  
Spectral Data ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Hydroxamic Acids ◽  
Aryl Ring ◽  
Independent Synthesis ◽  
Unambiguous Assignment

The reactions of O-alkylarylhydroxamic acids with a variety of alkylating agents, to yield mixtures of the N,O-dialkyl and 0,O'-dialkyl products, are described. Spectral data and independent synthesis allow the unambiguous assignment of structure to these isomeric products. Substituents on the aryl ring exert an electronic influence on the ratio of the two products; the extent of this influence varies with the alkylating agent. Diazomethane, triethyloxonium tetrafluoroborate and methyl fluorosulphonate give largely, but not exclusively, the 0,O'-dialkyl product. Methyl fluorosulphonate, in the presence of a base, reacts further to form an unstable salt which appears also to function as an alkylating agent.

scholarly journals Endotoxin Stimulation in Patients With Lymphoma: Correlation With the Myelosuppressive Effects of Alkylating Agents

Blood ◽  
1972 ◽  
Vol 39 (5) ◽  
pp. 602-609 ◽  
Author(s):  
Ronald C. DeConti ◽  
Stephen R. Kaplan ◽  
Paul Calabresi
Keyword(s):  
Bone Marrow ◽  
Hodgkin's Disease ◽  
Alkylating Agent ◽  
Hodgkin’S Disease ◽  
Alkylating Agents ◽  
Previous Therapy ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Made In

Abstract Estimates of the bone marrow granulocyte reserve were made in 97 patients with lymphoma utilizing the endotoxin Pyrexal. Normal granulocyte responses were observed in most patients who had not received prior myelosuppressive therapy. Patients with lymphosarcoma responded as well as those with Hodgkin’s Disease. All patients with leukopenia due to previous therapy or marrow infiltration failed to respond. In the absence of leukopenia only 47% of previously treated patients achieved normal responses. The severity of granulocytopenia produced by intravenous alkylating agent therapy was correlated with pretreatment Pyrexal responses. Patients with normal granulocyte reserves, as demonstrated by this test, tolerated subsequent chemotherapy with significantly less severe granulocytopenia (p <0.02) than patients with abnormal test responses. Nadir granulocyte values below 1000 cells/cu mm developed in 7 of 33 patients with normal Pyrexal responses and in 11 of 15 abnormal responders, despite comparable pretreatment granulocyte values.

scholarly journals Evaluation of extracorporeal alkylation of red cells as a potential treatment for sickle cell anemia

Blood ◽  
1976 ◽  
Vol 47 (3) ◽  
pp. 481-488 ◽  
Author(s):  
S Charache ◽  
R Dreyer ◽  
I Zimmerman ◽  
CK Hsu
Keyword(s):  
Cell Survival ◽  
Alkylating Agent ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Red Cells ◽  
Red Cell ◽  
Cell Life ◽  
Red Cell Survival ◽  
Toxic Reactions ◽  
Unacceptable Toxicity

Abstract Nitrogen mustard and nor-nitrogen mustard inhibit sickling, but the concentrations required would be associated with unacceptable toxicity if these agents were administered to patients. Red cells could be treated extracorporeally and infused back into donors, if the alkylating agent could be removed or inactivated, if the treatment per se did not significantly shorten red cell survival, and if viable alkylated lymphocytes could be eliminated from the treated blood. To estimate whether these conditions could be met in a clinical trial, red cells from four dogs were alkylated at 6-wk intervals. No toxic reactions were observed, although not all nor-nitrogen mustard was removed by the washing procedure. Red cell survival was shortened to about half that of control cells, using concentrations of alkylating agent which reduce sickling by 50%. Lymphocytes from treated blood could still exclude trypan blue, but could not be shown to circulate after reinfusion into donor dogs. If alkylating agents are used to treat patients' cells, inhibition of sickling may outweigh the shortening of red cell life span induced by the treatment; blood should probably be irradiated before infusion to avoid administration of alkylated and potentially mutated, but viable, lymphocytes.

Single, sequential, and multiple alkylating agent therapy for multiple myeloma: a CALGB Study.

1986 ◽  
Vol 4 (9) ◽  
pp. 1331-1339 ◽  
Author(s):  
M R Cooper ◽  
O R McIntyre ◽  
K J Propert ◽  
S Kochwa ◽  
K Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Single Agent ◽  
Cost Savings ◽  
Initial Therapy ◽  
Myeloma Protein ◽  
Fourth Group ◽  
To Receive ◽  
Agent Treatment

Four intravenous (IV) alkylating agent regimens were tested in 615 previously untreated patients with multiple myeloma. Patients were randomized to receive melphalan, cyclophosphamide, and carmustine in combination (MCBP), sequentially (Seq-MCBP), or in combination with doxorubicin (MCBPA). The fourth group received IV melphalan (MP) as the only alkylating agent. All groups received a tapering dose of prednisone. Toxicity was similar for all regimens although the nadir of cytopenia was reached more quickly for the regime including melphalan only. Response as measured by reduction in myeloma protein or other parameters were similar for the four treatments. Survival was significantly poorer for the group receiving the alkylating agents in sequence. The survival of high tumor cell load patients who were azotemic was better in the groups treated with IV MP or with the combination of IV MCBP. In view of the simplicity and probable cost savings attached to single-agent treatment, a melphalan/prednisone regimen should be considered as initial therapy for all patients with myeloma.

The preparation of reduced and S-alkykated wool keratins using Tri-n-butylphosphine

1966 ◽  
Vol 19 (12) ◽  
pp. 2355 ◽  
Author(s):  
JA Maclaren ◽  
BJ Sweetman
Keyword(s):  
Alkylating Agent ◽  
Alkylating Agents ◽  
Thiol Groups ◽  
Wool Keratin

When tri-n-butylphosphine is used to reduce the disulphide groups in wool keratin, several different methods can be used for the subsequent alkylation of the thiol groups formed. A novel feature is that in some oases reduction and alkylation can be effected using tri-n- butylphosphine and the alkylating agent acting simultaneously. S-Alkyl kerateines have been prepared using 11 alkylating agents of various chemical types. By means of such a technique a quantitative and apparently specific conversion of cystinyl residues in wool keratin to S.(2-aminoethyl)cysteinyl residues has been achieved.

Bendamustine Is Not Associated With An Increase In Infections – Systematic Review and Meta-Analysis Of Randomized Controlled Trials

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5125-5125 ◽  
Author(s):  
Anat Gafter-Gvili ◽  
Ronit Gurion ◽  
Pia Raanani ◽  
Ofer Shpilberg ◽  
Liat Vidal
Keyword(s):  
Systematic Review ◽  
Randomized Controlled Trials ◽  
Alkylating Agent ◽  
Meta Analysis ◽  
Alkylating Agents ◽  
Cochrane Library ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Solid Malignancies ◽  
Grade 3

Abstract Background Bendamustine is a chemotherapeutic drug with structural similarities to both alkylating agents (nitrogen mustard derivative) and purine analogues (benzimidazole ring). Theoretically, due to its nucleoside-like properties it might be associated with more infections. Data in the literature is lacking regarding the infection-related adverse events of bendamustine-containing regimens. Thus, we aimed to assess this risk. Methods Systematic review and meta-analysis of all randomized controlled trials comparing bendamustine containing regimens (alone or combined with other chemotherapeutic agents and/or rituximab) to any other regimens. Trials evaluating bendamustine for any indication (hematological as well as solid malignancies) were included.  A comprehensive search of The Cochrane Library, MEDLINE, conference proceedings and references was conducted until July 2013. Two reviewers appraised the quality of trials and extracted data. Outcomes assessed were: any infections, grade 3-4 infections, fatal infections, grade 3-4 neutropenia and grade 3-4 lymphopenia. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. We used fixed effect model to pool data, unless there was significant heterogeneity, in which case we used the random effects model. Results Ten trials conducted between the years 1998 and 2013 and randomizing 2360 patients were included. We included 4 trials of patients with non-Hodgkin lymphoma (Rummel 2013, Rummel 2010, Herold 2006 and the Bright study 2013), 3 trials of CLL (Knauf 2009, Niederle 2013, LeBlond 2013), 1 trial of patients with multiple myeloma (Ponish 2006) and 2 trials of breast carcinoma patients. The bendamustine arm included: bendamustine alone (2 trials), bendamustine-rituximab (BR) (4 trials), bendamustine, vincristine, prednisone (BOP) (1 trial), bendamustine, MTX. 5FU (BMF) (2 trials) and bendamustine, prednisone (BP) (1 trial). The comparator arms in 8 of the trials included other alkylating agents: chlorambucil, R -CHOP,  cyclophosphamide, MTX, 5-FU (CMF) and melphalan-prednisone (MP) – each regimen used in 2 trials and COP used in 1 trial.  In 2 trials the comparator arm included fludarabine based regimens (alone or with rituximab). There was no statistically significant effect for bendamustine on the rate of any type of infection (RR 1.06 [95% CI 0.83, 1.34], 6 trials, figure). This analysis included only trials of hematological malignancies. There was no increase in the rate of grade 3-4 infections (RR 1.45 [95% CI 0.86, 2.45], 7 trials) or fatal infection (RR 0.69 [95% CI 0.30, 1.58], 3 trials). Data were too scarce to analyze by specific types of infections separately. There was no increase in the rate of grade 3-4 neutropenia in the bendamustine arm (RR 0.9 [95% CI 0.58, 1.42], 6 trials). This was true both when the comparator was alkylating agent containing regimens (RR 0.87 [95% CI 0.52, 1.48], 4 trials) or fludarabine containing regimens (RR 1.02 [95% CI 0.54, 1.91], 2 trials). There was a significant increase in grade 3-4 lymphopenia in the bendamustine arm compared to alkylating agent containing regimens (RR 1.95[95% CI 1.54, 2.47). Conclusions Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared to either alkylating agents or fludarabine,  in hematological as well as in solid malignancies, despite an increase in lymphopenia. Thus, bendamustine remains a safe therapeutic option. The main drawback of this meta-analysis is the heterogeneity between malignancies and treatments. Disclosures: No relevant conflicts of interest to declare.

Ifosfamide versus cyclophosphamide: Long term gonadal effects in 166 male survivors of childhood cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9515-9515 ◽  
Author(s):  
V. Ridola ◽  
A. S. Defachelles ◽  
C. Schmitt ◽  
O. Fawaz ◽  
J. C. Gentet ◽  
...  
Keyword(s):  
Cumulative Dose ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
The Other ◽  
Median Dose ◽  
Male Survivors ◽  
Gonadal Dysfunction ◽  
Survivors Of Childhood Cancer ◽  
Gonadal Damage

9515 Background: Alkylating agents are associated with a risk of male gonadal damage, even in patients treated during childhood. The purpose of this work was to compare this risk after treatment by ifosfamide vs cyclophosphamide during childhood. Methods: Evaluation was based on basal FSH measurement known for its correlation with spermatogenesis. LH and testosterone were also measured in most of the patients. 159 males were evaluated after treatment of a soft tissue sarcoma (79), osteoasarcoma (39), ewing (10), lymphoma (28), other (3). 100 patients received ifosfamide as unique alkylating agent and the other 59 received cyclophosphamide as the other unique alkylating agent between 1973 and 2000. Median age at treatment was 11.2 years (0–18 yrs). Median interval after the end of the treatment was 10.7 years (4.1–20.2 yrs), median age at evaluation was 21.4 years (17.5–36.1 yrs). Median dose of ifosfamide was 54 g/m2 (18- 114), median dose of cyclo was 8.3 g/m2 (4.6–22). Age at treatment and at evaluation were similar in both groups. Results: All males but two (17.5 and 26.5 yrs) had normal testosterone levels. LH was elevated in 14% of the patients. FSH was above laboratory upper limit in 28 of the 59 males (47.5%) treated with cyclophosphamide and was within the normal range in 94 of 100 patients (94%) treated with ifosfamide. Eight patients treated with cyclophosphamide fathered children. The median dose of cyclo was 5.6 g/m2 (4.8 - 10.8 g/m2). Six patients who received 51 to 54 g/m2 fathered children. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide: only 2/16 boys (12%) who received more than 12 g/m2 had a normal dosage of FSH, while 29/43 (67%) of the boys who received lower doses of cyclo did so. Conclusions: These results show a low risk of gonadal dysfunction in men exposed to ifosfamide (median dose 54 g/m2) compared to the results for males treated with cyclophosphamide. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide. No significant financial relationships to disclose.

Alkylation of camphor imines of glycinates. Diastereoselectivity as a function of electronic factors in the alkylating agent

1986 ◽  
Vol 64 (4) ◽  
pp. 726-731 ◽  
Author(s):  
John M. McIntosh ◽  
Pratibha Mishra
Keyword(s):  
Transition State ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Type Systems ◽  
Alkyl Halides ◽  
State Interaction ◽  
Tert Butyl ◽  
Ca 50

Alkylation of the (R)-camphor imine of tert-butyl glycinate with a variety of alkylating agents gave diastereoselectivities ranging from 0–100%. Simple alkyl halides larger than methyl give de's (diastereomeric excesses) of ca. 50% whereas those derived from allylic type systems afford de's of 75–100%. The results are best explained by invoking a transition state interaction between the π system of the alkylating agent and the imine which, for steric reasons, requires alkylation to occur from the pro-R face.

scholarly journals P14.108 Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii93-iii94
Author(s):  
K Seystahl ◽  
B Hentschel ◽  
S Loew ◽  
D Gramatzki ◽  
J Felsberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Recurrent Glioblastoma ◽  
Mgmt Promoter Methylation ◽  
University Hospital ◽  
Mgmt Promoter ◽  
First Recurrence

Abstract BACKGROUND The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status PATIENTS AND METHODS We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n=260) or bevacizumab without or with irinotecan (n=84) for first recurrence of glioblastoma. Outcome was stratified for MGMT status and cross-over to bevacizumab or alkylators at further tumor progression. RESULTS Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agent chemotherapy at first recurrence was longer than for patients receiving bevacizumab (11.1 versus 7.4 months, p<0.001). The use of alkylating agents was associated with longer PRS-1 for patients with a methylated versus an unmethylated MGMT promoter (p=0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in the group receiving alkylating chemotherapy compared to bevacizumab for patients with a methylated (p<0.001) or unmethylated MGMT promoter (p=0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p=0.002). CONCLUSION This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of a methylated MGMT promoter.

Lone-pair cooperativity in the N-alkylation of some derivatives of 2,2'-biimidazole

1981 ◽  
Vol 34 (12) ◽  
pp. 2569 ◽  
Author(s):  
LW Deady
Keyword(s):  
Steric Hindrance ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Lone Pair ◽  
Lone Pairs ◽  
Close Proximity ◽  
Alkylation Reactions ◽  
Rate Ratios ◽  
Derivatives Of

The relative rates of N-alkylation of 1,1'-dimethyl-2,2'-biimidazole (6), 5,6-dihydrodiimidazo- [1,2-a:2',1'-c]pyrazine (7) and 6,7-dihydro-5H-diimidazo[l,2-a:2',1'-c][l,4]diazepine (8) with a variety of alkylating agents are reported. Irrespective of the alkylating agent, the order of reactivity was (8) (where the biimidazole has an additional three-carbon bridge) > (7) (two-carbon bridge) > (6) (no bridge), with a maximum of (8)/(6) = 317 for reaction with chloro(methoxy)methane. Since reaction of (8) is most susceptible to steric hindrance, but where the nitrogen lone pairs are in close proximity, these results support the idea of lone-pair cooperativity in the alkylation reactions. Variation in the rate ratios with changes in alkylating agent are discussed.

Linear Growth of Children With Nephrotic Syndrome: Effect of Alkylating Agents

PEDIATRICS ◽  
1989 ◽  
Vol 84 (3) ◽  
pp. 495-499
Author(s):  
Rafael Padilla ◽  
Andrew S. Brem
Keyword(s):  
Nephrotic Syndrome ◽  
Side Effects ◽  
Growth Velocity ◽  
Alkylating Agent ◽  
Linear Growth ◽  
Alkylating Agents ◽  
Velocity Measurements ◽  
Short Term ◽  
Mesangial Proliferation ◽  
Igm Deposits

Growth velocity measurements were assessed in 12 children with steroid responsive but frequent relapsing or dependent nephrotic syndrome prior to and following treatment with either cyclophosphamide or chlorambucil and alternate day prednisone. Patients averaged 6 ± 3 years (mean ± SD) of age at the time of treatment. All of the patients underwent renal biopsy prior to treatment; 5 of the 12 showed mesangial proliferation; and in 10 of the 12, IgM deposits were seen within the mesangium of the glomerulus. Growth rates before treatment with the alkylating agent were 4.3 ± 1.3 cm/y increasing to 8.7 ± 2.5 cm/y (P &lt; .001) after therapy despite the relapses that occurred in 5 of the patients in the year following treatment. Short-term side effects of the treatment were minimal. The significant increase in growth associated with diminished use of steroids makes the use of alkylating agents reasonable for children with nephrosis who show signs of decreased growth velocity.

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