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Angewandte Chemie (International Ed. in... Feb 20233-Substituted 2H-azirines can be considered strained cyclic ketimines, and highly enantioselective addition reactions of silicon nucleophiles to either acyclic or cyclic...
3-Substituted 2H-azirines can be considered strained cyclic ketimines, and highly enantioselective addition reactions of silicon nucleophiles to either acyclic or cyclic ketimines have been elusive so far. The present work closes this gap for those azirines by means of a copper-catalyzed silylation using a silyl boronic ester as a latent silicon nucleophile. The resulting C-silylated, unprotected (N-H) aziridines are obtained in high yields and with excellent enantioselectivities and can be further converted into valuable compounds with hardly any erosion of the enantiomeric excess.
PubMed: 36507717
DOI: 10.1002/anie.202215032 -
Angewandte Chemie (International Ed. in... Feb 2023The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds...
The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two-step one-pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross-coupled with an aryl triflate through C-C σ-bond alkoxy- or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring-opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three-dimensional structures into target molecules.
PubMed: 36507714
DOI: 10.1002/anie.202217064 -
Haematologica Apr 2023
Topics: Humans; Rituximab; Thiotepa; Methotrexate; Cytarabine; Central Nervous System Neoplasms; Lymphoma; Central Nervous System; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36453110
DOI: 10.3324/haematol.2022.282014 -
Beilstein Journal of Organic Chemistry 2022Cyclooctene endoperoxide was used as the key compound for the synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol. Reduction of the cyclooctene...
Cyclooctene endoperoxide was used as the key compound for the synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol. Reduction of the cyclooctene endoperoxide, prepared by photooxygenation of -1,3-cyclooctadiene, with zinc gave a cyclooctenediol and then benzylation of the hydroxy group yielded dibenzylated cyclooctene. Oxidation of the latter compound by OsO/NMO followed by mesylation of the hydroxy group provided bis(benzyloxy)cyclooctane-1,2-diyl dimethanesulfonate. Reaction of the bis(benzyloxy)cyclooctane-1,2-diyl dimethanesulfonate with NaN gave 2-azido-3,8-bis(benzyloxy)cyclooctyl methanesulfonate. Reduction of the azide group and debenzylation to give an amine provided the new 3-aminocyclooctanetriol. Treatment of the 2-azido-3,8-bis(benzyloxy)cyclooctyl methanesulfonate with Zn/NHCl and debenzylation resulted in the target aziridinecyclooctanediol.
PubMed: 36447522
DOI: 10.3762/bjoc.18.163 -
Acta Haematologica 2023
High Incidences of Acute and Chronic Graft-Versus-Host Disease after Hematopoietic Cell Transplants for Acute Myeloid Leukemia Using Thiotepa, Busulfan, and Fludarabine Pretransplant Conditioning.
Topics: Humans; Busulfan; Thiotepa; Hematopoietic Stem Cell Transplantation; Bronchiolitis Obliterans Syndrome; Incidence; Leukemia, Myeloid, Acute; Vidarabine; Transplantation Conditioning; Graft vs Host Disease; Retrospective Studies
PubMed: 36446340
DOI: 10.1159/000528306 -
Bone Marrow Transplantation Feb 2023Among pediatric malignancies, solid tumors, particularly within the central nervous system (CNS), are common. Thiotepa, a myeloablative, high-dose chemotherapeutic (HDT)...
High-dose thiotepa, in conjunction with melphalan, followed by autologous hematopoietic stem cell transplantation in patients with pediatric solid tumors, including brain tumors.
Among pediatric malignancies, solid tumors, particularly within the central nervous system (CNS), are common. Thiotepa, a myeloablative, high-dose chemotherapeutic (HDT) treatment administered prior to autologous hematopoietic stem cell transplantation (HSCT), can cross the blood-brain barrier and rapidly penetrate the CNS. We evaluated thiotepa HDT in conjunction with melphalan in Japanese patients with pediatric CNS/non-CNS solid tumors in a multicenter, open-label, non-comparative study. Thiotepa (200 mg/m/day) was administered intravenously (IV) over 24 h on days -12, -11, -5, and -4 before scheduled HSCT. Melphalan (70 mg/m/day) was administered IV over 1 h on days -11, -5, and -4. The safety analysis population comprised 41 patients, of whom 16 (39.0%) had solid tumors and 25 (61.0%) had brain tumors. The most frequently reported adverse events were diarrhea (40/41 [97.6%] patients) and febrile neutropenia (34/41 [82.9%]). No unexpected safety events were observed, and no events resulted in death or treatment discontinuation. All patients experienced bone marrow suppression and 39/41 (95.1%) achieved engraftment (neutrophil count ≥500/mm for 3 consecutive days after HSCT). The survival rate at day 100 post-autologous HSCT was 100%. These data confirm the safety of IV thiotepa plus melphalan HDT prior to autologous HSCT for patients with pediatric CNS/non-CNS solid tumors. Trial registration: JapicCTI-173654.
Topics: Child; Humans; Melphalan; Thiotepa; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Central Nervous System Neoplasms; Combined Modality Therapy
PubMed: 36329150
DOI: 10.1038/s41409-022-01820-5 -
Haematologica Mar 2023
Topics: Humans; Thiotepa; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Lymphoma; Central Nervous System; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Stem Cell Transplantation
PubMed: 36300776
DOI: 10.3324/haematol.2022.281640 -
Molecules (Basel, Switzerland) Oct 2022Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in...
Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the -position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.
Topics: Pyrroles; Lewis Acids; Aziridines; Biological Products; Water
PubMed: 36296466
DOI: 10.3390/molecules27206869 -
International Journal of Molecular... Oct 2022The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as...
The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed against cancer. However, to the best of our knowledge, aziridine derivatives showing inhibitory activity towards proteasome have never been described before. Herein we report a new class of selective and nonPIs bearing an aziridine ring as a core structure. In vitro cell-based assays (two leukemia cell lines) also displayed anti-proliferative activity for some compounds. In silico studies indicated non-covalent binding mode and drug-likeness for these derivatives. Taken together, these results are promising for developing more potent PIs.
Topics: Humans; Proteasome Inhibitors; Proteasome Endopeptidase Complex; Antineoplastic Agents; Aziridines; Neoplasms; Alkylating Agents; Ubiquitins
PubMed: 36293216
DOI: 10.3390/ijms232012363 -
Radiation Oncology (London, England) Oct 2022Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy. Although potentially curable, its prognosis remains dismal. Its treatment is based... (Observational Study)
Observational Study
The role of whole-brain radiotherapy (WBRT) in primary central nervous system lymphoma: is it an alternative to ASCT for consolidation following HD-methotrexate based induction in low-income settings?
BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy. Although potentially curable, its prognosis remains dismal. Its treatment is based on high-doses of methotrexate (HD-MTX) and rituximab, followed by consolidation therapy with whole-brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Currently, there is no consensus about the best consolidation strategy, but better outcomes with ASCT are obtained with conditioning regimens based on thiotepa, a high-cost drug with restricted use in resource-constrained settings. Latin American data on clinical outcomes, prognostic factors, and therapeutic management in PCNSL are virtually unknown.
METHODS
This is a retrospective, observational, and single-center study involving 47-Brazilian patients with PCNSL. We aim to assess outcomes, determine predictors of survival, and compare responses, as well as toxicities in patients consolidated with chemotherapy alone versus chemotherapy plus WBRT.
RESULTS
The median age at diagnosis was 59 years (24-88 years), and 53.1% were male. LDH ≥ UVN occurred in 44.7%, ECOG ≥ 2 in 67.6%, and 34.1% had multifocal disease. Hemiparesis was the main clinical presentation, observed in 55.3%, 51.0% had intermediate-/high-risk IELSG prognostic score, and 57.6% had an ABC-like phenotype by IHC. With a median follow-up of 24.4 months, estimated 5-year OS and PFS were 45.5% and 36.4%, respectively. Among 40 patients treated with HD-MTX-based induction, estimated 2-year OS was 85.8% for those consolidated with WBRT plus HIDAC versus only 41.5% for those consolidated with HIDAC alone (p < 0.001). Hematologic and non-hematologic toxicities were not significant, and severe cognitive impairment occurred in only 6.3% (3/47) of cases, all of them treated with WBRT. Age < 60 years, Hb ≥ 120 g/L and WBRT consolidation were associated with increased OS, however, LDH ≥ UVN, hypoalbuminemia, ECOG ≥ 2, Karnofsky PS < 70 and intermediate-/high-risk Barcelona score were associated with decreased OS.
CONCLUSION
Combined consolidation therapy (CCT) based on WBRT plus HIDAC was associated with increased OS in PCNSL compared to isolated consolidation therapy (ICT) based on HIDAC alone. Here, severe late neurotoxicity was uncommon with this approach. These data suggest that WBRT may be an effective and safe alternative to ASCT for consolidation therapy in PCNSL, particularly in resource-constrained settings, where access to thiotepa for pre-ASCT conditioning is not universal.
Topics: Male; Female; Humans; Transplantation, Autologous; Thiotepa; Methotrexate; Hematopoietic Stem Cell Transplantation; Central Nervous System Neoplasms; Rituximab; Antineoplastic Combined Chemotherapy Protocols; Stem Cell Transplantation; Combined Modality Therapy; Lymphoma; Brain; Central Nervous System
PubMed: 36273167
DOI: 10.1186/s13014-022-02142-y