Alkylating Activity Research Articles

Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme-A Literature Review and Clinical Outcomes.

Glioblastoma multiforme (GBM) is one of the most aggressive primary tumors of the central nervous system. It is associated with a very poor prognosis, with up to half of patients failing to survive the first year after diagnosis. It develops from glial tissue and belongs to the adult-type diffuse glioma group according to the WHO classification of 2021. Therapy for patients with GBM is currently based on surgical resection, radiation therapy, and chemotherapy, but despite many efforts, there has been minimal progress in tumor management. The most important chemotherapeutic agent in the treatment of this tumor is temozolomide (TMZ), a dacarbazine derivative that presents alkylating activity. It is usually administered to patients concurrently with radiation therapy after surgical resection of the tumor, which is defined as the Stupp protocol. Temozolomide demonstrates relatively good efficacy in therapy, but it could also present with several side effects. The resistance of GBM to the drug is currently the subject of work by specialists in the field of oncology, and its use in various regimens and patient groups may bring therapeutic benefits in the future. The aim of this review paper is to summarize the relevance of TMZ in the treatment of GBM based on recent reports.

Regulating acid properties of ZSM-5 nanosheets by Fe incorporation towards high-performance alkylation of benzene with methanol

A clear understanding of the acidity-activity relationship is an important prerequisite for designing functional materials in alkylation of benzene with methanol. Herein, a series of b-axis-oriented [Fe/Al]-MFI nanosheets with similar thickness but varied acidities were prepared by tuning Fe incorporation to systematically study the effect of acidity on their alkylation performance. Comprehensive physiochemical studies demonstrate that tetrahedral framework type Fe species are dominated. The incorporation of Fe significantly weakens the strong acid strength of zeolite thus endowing the samples with proper acidity, consequently showing a strong inhibition effect on the by-product ethylbenzene. Moreover, a long-term stable operation (>300 h) is further achieved over the [Fe]-S-1 nanosheets by optimizing the content of framework Fe. This work elucidates the important relationship between acidity and alkylation activity.

Measurement of ThioTEPA and Its Metabolite TEPA in Plasma and Cerebrospinal Fluid by Turbulent Flow Chromatography-Tandem Mass Spectrometry.

N,N',N''-Triethylenethiophosphoramide (thioTEPA) is a polyfunctional, organophosphorus alkylating agent that has been a primary treatment of multiple solid malignancies for many years and more recently as part of conditioning regimens prior to hematopoietic stem cell transplantation for a variety of hematologic malignancies. In vivo, thioTEPA is quickly metabolized to N,N',N″-triethylenephosphoramide (TEPA). ThioTEPA and TEPA have similar alkylating activity and both exhibit outstanding central nervous system penetration. Therefore, it is possible and desirable to monitor both compounds in plasma and cerebrospinal fluid (CSF).This chapter describes a method to measure both compounds simultaneously. ThioTEPA and TEPA are extracted with solvent from plasma and CSF by the addition of deuterated internal standards prepared in methanol. Chromatographic separation is attained using a C18 column and mass spectrometry which is performed in the positive ion mode. Herein, we describe a fast, accurate, and sensitive assay to quantify both compounds in plasma and CSF by turbulent flow LC-MS/MS which allows for fast and accurate therapeutic drug monitoring and timely dose modifications.

Molecular design and experimental study on the alkylation of benzene with C6 olefin dimer with Lewis acidic monoamine ionic liquids and its sulfonate surfactant properties

Long-chain alkyl benzene (LAB), conventionally manufactured by petrochemical routes, is an important intermediate for the synthesis of high-value chemicals, especially detergents and oil displacement agents. The preparation of LAB from coal-based olefins has attracted extensive research interest. In this work, the alkylation activity of four Lewis acidic monoamine chloroaluminate ionic liquids (LAMCILs), designed by AlCl3 and monoamine hydrochloride with alkyl chains of different lengths, was predicted by quantum chemical calculations using the synthesis of 1-methyl-1-butylheptylbenzene (MBHB) with benzene and C6 olefin dimer as a model reaction. The HOMO*-LUMO* gap indicated that the alkylation activity was enhanced with increasing alkyl chain length of the organic amine molecules in the LAMCILs, in the following order: [n-C6H13NH3]Cl-AlCl3 > [n-C4H9NH3]Cl-AlCl3 > [n-C3H7NH3]Cl-AlCl3 > [C2H5NH3]Cl-AlCl3. These four LAMCILs were successfully synthesized and used to catalyze the alkylation of benzene with the C6 olefin dimer. The experimental results are consistent with the calculated results. The UV/VIS characterization showed that their Hammett acidity function (H0) increased as the alkyl chain of organic monoamine molecules in the LAMCILs extended. Therefore, a two-way correlation between the HOMO*-LUMO* gap, MBHB yield and Hammett acidity function can be established. Furthermore, the effect on the yield of MBHB was investigated by the method of metal chloride modified [n-C4H9NH3]Cl-AlCl3 ionic liquids. The results showed that the CuCl2-modified [n-C4H9NH3]Cl-AlCl3 ionic liquid had better catalytic activity in this study. Under optimal reaction conditions, the conversion of the C6 olefin dimer and selectivity toward MBHB reached 100 % and 91.34 %, respectively. Finally, the surfactant properties of sodium 1-methyl-1-butylheptylbenzene sulfonate (SMBHBS) were examined, and the results indicated that its surfactant properties were basically comparable to those of commercial LAS.

O-46 - Novel Radiofluorination via Electrophilic Activation of Alkyl Phosphates/Phosphonate

O-46 - Novel Radiofluorination via Electrophilic Activation of Alkyl Phosphates/Phosphonate

Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide-Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma.

Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the β phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.

Studying the Interaction between Bendamustine and DNA Molecule with SERS Based on AuNPs/ZnCl2/NpAA Solid-State Substrate.

Bendamustine (BENDA) is a bifunctional alkylating agent with alkylating and purinergic antitumor activity, which exerts its anticancer effects by direct binding to DNA, but the detailed mechanism of BENDA-DNA interaction is poorly understood. In this paper, the interaction properties of the anticancer drug BENDA with calf thymus DNA (ctDNA) were systematically investigated based on surface-enhanced Raman spectroscopy (SERS) technique mainly using a novel homemade AuNPs/ZnCl2/NpAA (NpAA: nano porous anodic alumina) solid-state substrate and combined with ultraviolet-visible spectroscopy and molecular docking simulation to reveal the mechanism of their interactions. We experimentally compared and studied the SERS spectra of ctDNA, BENDA, and BENDA-ctDNA complexes with different molar concentrations (1:1, 2:1, 3:1), and summarized their important characteristic peak positions, their peak position differences, and hyperchromic/hypochromic effects. The results showed that the binding modes include covalent binding and hydrogen bonding, and the binding site of BENDA to DNA molecules is mainly the N7 atom of G base. The results of this study help to understand and elucidate the mechanism of BENDA at the single-molecule level, and provide guidance for the further development of effective new drugs with low toxicity and side effects.

Constructing silanol nests on ZSM-5 catalyst by deboronation for stable alkylation of toluene with methanol

Dealuminization over aluminium-containing ZSM-5 could create silanol nests and improve catalytic activity for alkylation of toluene with methanol. However, obviously damaged microporous structure seriously accelerated catalyst deactivation. Here, we demonstrate highly stable alkylation on ZSM-5 by deboronation treatment over boron-containing ZSM-5.11B MAS NMR, 1H MAS NMR and OH-IR suggested that silanol nests with hydrogen bonds were created at the expenses of the removal of skeleton-B atoms. The formed silanol nests promote the adsorption of toluene, inhibit the methanol self-reaction and corresponding the deep alkylation process. Therefore, alkylation efficiency and toluene conversion could reach 70.8% and 33.5%, respectively. Importantly, the microporous structure of deboronized ZSM-5 was well maintained during deboronation, which determined a greatly improved catalytic stability compared with that of traditional dealuminized ZSM-5. Moreover, the deboronized ZSM-5 still presented relatively good catalytic stability under a higher methanol feedstock although the coke deposition was accelerated.

Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics.

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future.

New Perspective on Comparative Chemometric and Molecular Modeling of Antifungal Activity and Herbicidal Potential of Alkyl and Cycloalkyl s-Triazine Derivatives

The contamination of the environment by pesticides is becoming a burning issue in many countries in the World. Development, design, and synthesis of new eco-friendly pesticides and modification of existing ones in order to improve their efficacy with the lowest impact on the environment are two main future possibilities in crop protection and the provision of sufficient food for the growing world population. The present study is focused on the comparative analysis of a series of eight symmetrical triazine derivatives, as potential herbicide candidates with acyclic (alkyl) and cyclic (cycloalkyl) substituents, in terms of their antifungal activity towards Aspergillus flavus as an opportunistic fungal pathogenic microorganism responsible for frequent contaminations of crops with aflatoxin, and in terms of their potential application as herbicides in maize, common wheat, barley, and rice crops. The applied methods include the chemometric pattern recognition method (hierarchical cluster analysis), experimental microbiological analysis of antifungal activity (agar well-diffusion method), and molecular docking of the triazines in the corresponding enzymes. The main findings of the conducted study indicate the significant antifungal activity of the studied triazine derivatives towards A. flavus, particularly the compounds with acyclic substituents; five out of eight studied triazines could be applied as systematic herbicides, while the other three triazines could be used as contact herbicides; the compounds with acyclic substituents could be more suitable for application for various crops protection than triazines with cyclic substituents.

Carmustine: Promising Drug for Treatment of Glioma

Background: The treatment for glioma has challenging and survival rate is not more than one year after diagnosis. Carmustine is a non-specific antineoplastic agent that belongs to the nitrosourea group of compounds (bischlo-roethyl nitrosourea) and has various mechanisms of tumor cytotoxicity. Main body: It can alkylate reactive sites on nucleoproteins as an alkylating agent, interfering with DNA and RNA synthesis and DNA repair. It can create interstrand crosslink’s in DNA, preventing DNA replication and transcription. Under physiological conditions, carmustine undergoes spontaneous nonenzymatic decomposition, releasing reactive intermediates with alkylating and carbamoylating activities, which are thought to be responsible for carmustine’s anticancer and cytotoxic properties. Human gliomas are the for the most part kind of tumor for brain. Gliomas can be treated with a variety of chemotherapeutics, but carmustine has recently emerged as a promising treatment option. Conclusion: The adoption of a nose-to-brain medication delivery method has several advantages over efforts that try to breach the blood-brain barrier. The focused strategy also lowers the risk of cardiovascular harm. A significant advantage of nose to brain administration is the relatively high patient compliance. Research into new chemotherapeutic compounds and treatment delivery technologies is crucial for present and future patients

Selective production of 2-(tert-butyl)-3-methylphenol from depolymerization of enzymatic hydrolysis lignin with MoS2 catalyst

Low selectivity and complex product distribution are the main challenges for the utilization of lignin. Herein, the selective production of 2-(tert-butyl)-3-methylphenol (TBC), an antioxidant in the polymer industry, from depolymerization of enzymatic hydrolysis lignin (EHL) on a hydrothermally synthesized MoS2 catalyst is studied. The total aromatic monomer yield is 124.1 mg/g EHL and the selectivity of TBC is up to 40.3 wt% in methanol at 280 °C under 2 MPa H2 for 6 h. The FT-IR analysis of products reveals that MoS2 has a high activity for demethylation, dehydroxylation and alkylation, and the dimer conversions reveal that C-O and C-C bonds in EHL are broken with MoS2. The guaiacol and its derivants are identified as the intermediate for formation of TBC in EHL depolymerization according to the effect of time on product distribution and monomer conversion.

Synthesis of Nanocrystalline Mordenite Zeolite with Improved Performance in Benzene Alkylation and n‐Paraffins Hydroconversion

AbstractNanocrystalline mordenite (MOR) zeolites were hydrothermally synthesized in a single step with commercial cetyltrimethylammonium (CTA) hydroxide as the sole organic template, while the aluminum source was varied in a typical synthesis gel. CTA can effectively reduce the crystal growth of MOR zeolites, in some cases selectively in the a‐ and b‐directions of the unit cell. These nanocrystalline MOR zeolites do not only have a larger external surface area than their bulk counterparts prepared without CTA, but the Brønsted acid sites in the side‐pockets are also more accessible. The combination of the use of CTA and AlCl3 ⋅ 6H2O afforded the best‐performing catalyst with much improved activity in benzene alkylation and hydroconversion of n‐hexadecane (n‐C16). Modifying MOR synthesis with CTA hydroxide is a cheap and effective method to open up the one‐dimensional micropore system of mordenite, increasing the catalytic performance in hydrocarbon reactions.

Study on the alkylation of aromatic hydrocarbons and propylene

In order to improve the efficiency of the alkylation reaction to aromatic hydrocarbons and propylene, different types of catalysts were screened, including ultra-stable Y molecular sieves (USY), solid phosphoric acid (SPA), ZSM type molecular sieve (HZSM), etc. The effects of reaction temperature, catalyst loading, and reaction time on the conversion rate of aromatic hydrocarbons and the selectivity of target products were investigated using the high-pressure reaction device. The catalysts were characterized by XRD, BET, SEM, FT-IR, NH3-TPD, and other methods. The experimental results show that the USY catalyst exhibits higher catalytic activity for alkylation. This catalyst can be used for the alkylation of different aromatic hydrocarbons. Good conversion and selectivity can be obtained. Futhermore, in a six-cycle experiment, the USY catalyst was reused without loss of efficiency.

The Role of AQ in the Regioselectivity of Strong Alkyl C-O Bond Activation Catalyzed by Pd(OAc)2: A Density Functional Theory Mechanistic Study.

A density functional theory method was employed to investigate the mechanism of C-O bond activation of butanoic acid substrates bearing the 8-aminoquinoline (AQ) group catalyzed by Pd(OAc)2. The whole reaction consists of five fundamental steps: the chelation of substrate A1, the C-H activation step, the C-N coupling step, the protodepalladation step, and the release of the final product. The calculated results indicated that the protodepalladation step is the rate-determining step with a free energy barrier of 24.3 kcal/mol. This theoretical study pointed out that the energy barriers of C-H activation in the presence and absence of AQ are 11.3 and 26.6 kcal/mol, respectively. This is to say that the installation of the AQ directing group is critical to the regioselectivity of C-H activation and the β-O elimination steps, and this reason enables selective activation of the γ C-O bond. Furthermore, this chelating functionality facilitated the protodepalladation step because the energy barrier of the protodepalladation step was decreased with the coordination of the AQ directing group with a Pd center, and that was 39.3 kcal/mol in the absence of AQ. This also explains why no product formation was observed in the experiment upon changing the directing AQ group to a phenylamino group. Finally, other substrates bearing the phenol leaving group at the β- and δ-positions of carbonyl were investigated in order to expand the applicability of the AQ directing strategy. This work could provide new theoretical insights into the activation of strong alkyl C(sp3) covalent bonds via the AQ directing strategy.

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

Inclusion of bidentate phosphine molecules in the supercage of FAU zeolite

Bidentate phosphines (Ph 2 P(CH 2 ) n PPh 2 ) with different alkyl chain lengths (n = 1–10) were included in the supercage (SC) of FAU-zeolite. Thermal treatment of the mixture of a bidentate phosphines and FAU-zeolite at 443 K resulted in the inclusion of the former into the SC, with up to 0.75 molecules per SC. The included molecules were strongly bound by FAU-zeolite, with desorption observed at higher temperatures compared to those of unloaded ones. The specific surface area of the FAU-zeolite decreased linearly with an increase in the number of phosphines included. This tendency was more emphasized in phosphines with n = 6–10 compared with those with n = 1–5. A characteristic shift in the C–C stretching band of the benzene ring was observed in the Fourier-transform infrared spectroscopy (FT-IR) spectrum, due to the strong interaction between bidentate phosphines and FAU-zeolite; the extent was more when using *BEA-loaded ones. Formation of the inclusion compounds between bidentate phosphines and FAU zeolites was observed with the molecular dynamics (MD) calculations. The bidentate phosphines included in the SC of the FAU-zeolite were reacted with PdCl 2 to form Pd complexes. The detailed analysis of the Pd complexes with Pd K-edge EXAFS revealed a characteristic decrease in the Pd–Cl bond distance with the use of complexes with n = 3 and 4, suggesting that the local structure around Pd was distorted through the interaction of the Pd complexes with the pores of the FAU-zeolite. The Pd complexes included in the SC were active for allylic alkylation between allyl methyl carbonate and ethyl acetoacetate. • Bidentate phosphines could be directly included in the supercage of FAU zeolite. • Formation of the inclusion compound was simulated by MD calculation. • Pd complexes with bidentate phosphines in SCs of FAU zeolite exhibited activity in the allylic alkylation.

Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions

AbstractThe present study describes the kinetic analysis of the 3‐chloropiperidine alkylation mechanism. These nitrogen mustard‐based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide abstraction using silver salts with weakly coordinating anions lead to the isolation of these proposed intermediates, whereas their structure was confirmed by single crystal XRD. Kinetic studies of the aziridinium ions also revealed notable reactivity differences of the C5 gem‐methylated compounds and their unmethylated counterparts. The observed reactivity trends were also reflected by NMR studies in aqueous solution and DNA alkylation experiments of the related 3‐chloropiperidines. Therefore, the underlying Thorpe‐Ingold effect might be considered as another option to adjust the alkylation activity of these compounds.

TCL-361: Bendamustine as Front-Line Therapy in T-Cell Prolymphocytic Leukemia: A Monocentric Experience

Introduction T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell-neoplasm that is characterized by uncontrolled proliferation of mature T-cell lymphocytes with a very poor prognosis. Nowadays, alemtuzumab as a single agent is the best available option for both treatment-naive and relapsed/refractory patients; however, its efficacy is hampered by various adverse events (AEs) such as infusion-associated reactions, autoimmune AEs, and opportunistic infections. Objective We conducted a monocentric, retrospective study to evaluate the safety and efficacy of bendamustine, which is a bifunctional mechlorethamine derivative with alkylating and antimetabolite activities, as first-line therapy in patients unfit for alemtuzumab. Patients and Methods We collected clinical and biological data of 7 T-PLL patients treated with bendamustine between 2014 and 2020 in our institution. Four out of seven (57%) were males, the median age at diagnosis was 73 years (65–83 years). The median time from diagnosis to treatment was 15 months. Bendamustine was administered intravenously (90 mg/m2 on days one and two, every four weeks) for up to six cycles. Results Overall response rate was 57%, 3 patients achieved complete response (43%), and one partial response (14%). One patient experienced stable disease, and two patients progressed during treatment. Five patients (71%) experienced a relapse. Median overall survival (OS) was 63.7 months (19–108); median OS for responding patients was 187 months versus 24 months for non-responding patients (p=0.093). Median progression-free survival (PFS) was 12 months (11–13). Three patients received second-line therapy: one patient was treated with gemcitabine; the others received a second bendamustine course. Two patients received a third-line therapy with combination chemotherapy: COMP (prednisone, cyclophosphamide, vincristine, myocettm) and CVP (cyclophosphamide, vincristine, prednisone). Two patients experienced infusion-associated reactions. Four patients experienced hematological toxicities: one thrombocytopenia G3, 3 neutropenia G3 requiring G-CSF administration. Four patients received co-trimoxazole prophylaxis, one received acyclovir prophylaxis. One patient experienced herpetic retinitis. Premature termination ( Conclusions Our data are consistent with scientific literature. This treatment is feasible and safe, with an acceptable toxicity profile. Although alemtuzumab remains the standard of care of this rare disease, bendamustine might be a valid option either for unfit patients or for undeferrable disease.

Graphene oxide-assisted fast synthesis of hierarchical ZSM-11 with superior performance for benzene alkylation

Fast synthesis of zeolite with hydrothermal method is a challengeable topic. In this work, we reduced the crystallization time to ~1/3 of conventional method by adding a small amount of graphene oxide (GO) into ZSM-11 synthesis gel. The embedment of GO into ZSM-11 crystal was confirmed by XPS, TG, and Raman spectra, while it modified morphology, porosities, component, and surface acidity of ZSM-11 as characterized by SEM, TEM, XRF, N2-physisorbtion, NH3-TPD, and Py-IR. The non-classical nucleation, which governed the required crystallization time, was further proposed and evidenced by both experimental observations and molecular dynamic modeling. It clearly illustrated the positive role of GO on promoting the formation of meta-stable phase during non-classic nucleation, resulting into much shorter crystallization time. GO embedded ZSM-11 demonstrated high activity (reaction rate and TOF), improved selectivity, and superior stability for benzene alkylation with ethanol, which can be attributed to the regulated surface acidity and diffusion properties. This work opens up a new perspective to synthesize ZSM-11 zeolite with superior catalytic performance in a highly efficient and environmental manner.