ABSTRACT
In this study, we present the development of two catalytic processes: a Pd-PEPPSI-catalyzed aminocarbonylation and a Pd(OAc)2-Xantphos-catalyzed alkoxycarbonylation of d-glycals, utilizing carbonylative cross-coupling reactions. We explored successfully various types of aromatic amines, as well as alkyl amines and amino acids, to synthesize new d-glycal amides. However, we observed limitations in the reactivity of alkyl and heteroaromatic amines. The processes enabled the synthesis of 20 novel C1-branched glycoamides and 7 new d-gluco esters.
ABSTRACT
A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/chemistry , Janus Kinases , Purines/pharmacology , Cell Line, Tumor , Cell ProliferationABSTRACT
In this study, we present the development of two catalytic processes: a Pd-PEPPSI-catalyzed aminocarbonylation anda Pd(OAc)2-Xantphos-catalyzed alkoxycarbonylation of D-glycals, utilizing carbonylative cross-coupling reactions. We exploredsuccessfully various types of aromatic amines, as well as alkyl amines and amino acids, to synthesize new D-glycal amides. However,we observed limitations in the reactivity of alkyl and heteroaromatic amines. The processes enabled the synthesis of 20 novel C1-branched glycoamides and 7 new D-gluco esters.
ABSTRACT
We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a-d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.
Subject(s)
Antimalarials , Folic Acid Antagonists , Humans , Histone Deacetylase Inhibitors/pharmacology , Antimalarials/pharmacology , Hydroxamic Acids/pharmacology , Folic Acid Antagonists/pharmacology , Structure-Activity Relationship , Histone Deacetylase 1ABSTRACT
Glycal amides were prepared for the first time by reacting 2-iodo-D-glycals with L-amino acid esters via a Pd-catalyzed carbonylative cross-coupling reaction, by using Mo(CO)6 as the carbon monoxide source. Glycal amides were synthesized in moderate to good yields under our optimized conditions. In addition, the acetyl groups of the glucal amides could be readily removed to obtain the corresponding trihydroxy derivatives in good yields.
ABSTRACT
Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential anticancer HDACis. In addition, structure-activity relationship (SAR) studies have been performed in order to verify the influence of the linker on the biological profile of the compounds. All tested compounds demonstrated significant antiproliferative effects against solid and hematological human tumor cell lines. Among them, 11b exhibited nanomolar potency against hematological tumor cells including Jurkat and Namalwa, with IC50 values of 40 and 200 nM, respectively. Cellular and molecular proliferation studies, in presence of compounds 11a-d, showed significant cell growth arrest, apoptosis induction, and up to 43-fold selective cytotoxicity for leukemia cells versus non-tumorigenic cells. Moreover, compounds 11a-d increased acetylated α-tubulin expression levels, which is phenotypically consistent with HDAC inhibition, and indirectly induced DNA damage. In vitro enzymatic assays performed for 11b revealed a potent HDAC6 inhibitory activity (IC50: 8.1 nM) and 402-fold selectivity over HDAC1. Regarding SAR analysis, the distance between the hydroxamate moiety and the aromatic ring as well as the presence of the double bond in the cinnamyl linker were the most relevant chemical feature for the antiproliferative activity of the series. Molecular modeling studies suggest that cinnamyl hydroxamate is the best moiety of the series for binding HDAC6 catalytic pocket whereas exploration of Ser568 by the urea connecting unity (CU) might be related with the selectivity observed for the cinnamyl derivatives. In summary, cinnamyl hydroxamate derived compounds with HDAC6 inhibitory activity exhibited cell growth arrest and increased apoptosis, as well as selectivity to acute lymphoblastic leukemia cells. This study explores interesting compounds to fight against neoplastic hematological cells.
Subject(s)
Antineoplastic Agents/pharmacology , Cinnamates/pharmacology , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Cinnamates/chemical synthesis , Cinnamates/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase 1/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Trans-10, cis-12-conjugated linoleic acid (CLA) is a potent bioactive fatty acids (FA) that causes milk fat depression in lactating animals. FA are transferred to milk directly through chylomicrons and indirectly by recycling through other tissues. The objective of this study was to characterise the kinetics of trans-10, cis-12 CLA transfer to plasma and milk after a single bolus infusion. Five multiparous mid-lactation cows received a single abomasal bolus infusion of an enriched CLA mixture providing 15 g of trans-10, cis-12 CLA and 15 g of cis-9, trans-11 CLA over a 30-min period. Plasma concentration of trans-10, cis-12 and cis-9, trans-11 CLA peaked 2 h post-bolus, reaching 0·29 and 0·38 % of total plasma FA, respectively, and returned to pre-bolus values at 72 h post-infusion. Milk trans-10, cis-12 CLA yield and concentration peaked 14 h post-bolus (0·25 g/h) and was not detectable in milk after 86 h. Total apparent transfer of trans-10, cis-12 CLA to milk was 41 %, with 73 % transferred to milk through the direct pool (chylomicrons) and the remaining 27 % transferred through the indirect pool (tissue recycling). Compartmental modelling revealed the existence of a transient unavailable pool of trans-10, cis-12 CLA in extravascular tissues represented primarily by the mammary gland, which slowly exchanges with an available pool for secretion in milk fat and transfer to milk. In conclusion, trans-10, cis-12 CLA is predominantly transferred to milk through the direct pathway; however, how this CLA isomer is processed within the mammary gland requires further investigation.
Subject(s)
Abomasum/chemistry , Lactation , Linoleic Acids, Conjugated/chemistry , Milk/chemistry , Animals , Body Fluids , Cattle , Fats/chemistry , Female , Kinetics , Mammary Glands, Animal/physiology , Plasma/chemistryABSTRACT
BACKGROUND AND OBJECTIVES: The treatment of childhood cancers has increased survival rates, but also the risk of sequelae, such as endocrine complications. The objective of this study is to evaluate the endocrine disorders in survivors of childhood malignant tumors within the first years after treatment and analyze the variables related to their appearance. SUBJECTS AND METHODS: A retrospective medical record review of patients referred to pediatric endocrinology after treatment of malignancy. Outcome measures were frequency and types of endocrine dysfunction and new-onset obesity. Clinical and laboratory evaluations were performed every 6 months. Statistics tests were: chi square and multiple logistic regression. RESULTS: Fifty five patients (26 women) were included with an age at diagnosis of tumour (mean±standard deviation) 6.0±4.4 years and followed up for 6.8±3.6 years. Thirty endocrine disorders were diagnosed in 26 patients (47.3%), 17 women (P=.01). Eleven adolescents had primary hypogonadism (26.2% to 0.6±0.5 years of follow-up) in relation to local irradiation (adjusted odds ratio [OR] 3.99, P=.005). Eleven patients had a pituitary disorder (20.0%) 5.2±2.4 years after diagnosis in relation to brain irradiation (OR 1.54, P=.039). Six children (10.9%) had primary hypothyroidism from 3.2±1.0 years of follow-up. Two children developed obesity. CONCLUSIONS: Endocrine disorders are frequently seen within the first years after diagnosis of a childhood cancer, so hormonal evaluation should start early and be repeated periodically.
Subject(s)
Cancer Survivors , Endocrine System Diseases/etiology , Neoplasms/complications , Adolescent , Child , Child, Preschool , Endocrine System Diseases/diagnosis , Endocrine System Diseases/epidemiology , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Logistic Models , Male , Neoplasms/therapy , Retrospective Studies , Risk FactorsABSTRACT
The behavioral manifestations of autism, including reduced sociability (reduced tendency to seek social interaction), may be related to underdevelopment of the corpus callosum (CC). The BALB/cJ inbred mouse strain is a useful model system for testing the relationship between reduced sociability and CC underdevelopment. BALB/cJ mice show low levels of sociability, on average, but substantial intrastrain variability in sociability, as well as striking variability in CC development. This study tested the hypothesis that sociability is positively correlated with CC size within the BALB/cJ inbred strain. 30-day-old BALB/cJ and C57BL/6J mice were tested for sociability towards gonadectomized A/J stimulus mice in a social choice task. The size of the corpus callosum was measured histologically at the midsagittal plane. BALB/cJ mice showed a significant positive correlation between the tendency to sniff the stimulus mouse and size of the CC relative to brain weight. C57BL/6J mice showed consistently high levels of sociability and normal corpus callosum development. These results suggest that abnormal white matter structure is associated with deficits in sociability in BALB/cJ mice. Additional studies are warranted to elucidate the relationship between brain connectivity and sociability in this model system.