Differentiation of regioisomeric N-alkylation of some indazoles and pyrazolopyridines by advanced NMR techniques.

Indazole scaffold have two interconvertible tautomeric forms. Regioselectivities were determined for N-benzylations and alkylation of some non-substituted and substituted indazoles, under basic conditions (K2CO3) in DMF. The ratio of regioisomers occurrence between N1:N2 is almost equal. Their structures were established through a combination of NOESY and 1H-13C/15N HMBC NMR methods. Additionally, pyrazolo[3,4-b]pyridines have also three possible tautomeric forms; primarily 1H and 2H, with 7H isomers being rare. Pyrazolo[4,3-b]pyridines have only known two possible tautomeric forms so far; 1H and 2H.

Synthesis of novel indol-3-acetamido analogues as potent anticancer agents, biological evaluation and molecular modeling studies.

Cannabinoids bind to cannabinoid receptors CB1 and CB2 and their antitumoral activity has been reported against some various cancer cell lines. Some synthetic cannabinoids possessing indole rings such as JWH-015 and JWH-133 particularly bind to the cannabinoid CB2 receptor and it was reported that they inhibit the proliferation and growth of various cancer cells without their psychoactive effects. However, the pharmacological action mechanisms of the cannabinoids are completely unknown. In this study, we report the synthesis of some new cannabinoidic novel indoles and evaluate their anticancer activity on various cancerous and normal cell lines (U87, RPMI 8226, HL60 and L929) using several cellular and molecular assays including MTT assay, real-time q-PCR, scratch assay, DAPI assay, Annexin V-PE/7AAD staining, caspase3/7 activity tests. Our findings indicated that compounds 7, 10, 13, 16, and 17 could reduce cell viability effectively. Compound 17 markedly increased proapoptotic genes (BAX, BAD, and BIM), tumor suppressor gene (p53) expression levels as well as the BAX/BCL-2 ratio in U87 cells. In addition, 17 inhibited cell migration. Based on these results, 17 was chosen for determining the mechanism of cell death in U87 cells. DAPI and Annexin V-7AAD staining results showed that 17 induced apoptosis, moreover activated caspase 3/7 significantly. Hence, compound 17, was selected as a lead compound for further pharmacomodulation. To rationalize the observed biological activities of 17, our study also included a comprehensive analysis using molecular docking and MD simulations. This integrative approach revealed that 17 fits tightly into the active site of the CB2 receptor and is involved in key interactions that may be responsible for its anti-proliferative effects.

Synthesis of some new 2-(substituted-phenyl)imidazo[4,5-c] and [4,5-b]pyridine derivatives and their antimicrobial activities.

The synthesis of 5H-imidazo[4,5-c]pyridines analogues (1a - 1h) and 4H-imidazo[4,5-b]pyridines (3a - 3c) was achieved by reacting 3,4-diaminopyridine or 2,3-diaminopyridine with Na2S2O5 adduct of corresponding benzaldehydes (a1 - a8). Alkylation of compounds (1a - 1h) and (3a - 3c) using 4-chlorobenzyl and /or butyl bromide under basic conditions (K2CO3, DMF) predominantly resulted in the formation of N5 regioisomers (2a - 2l) and N4,3 regioisomers (4a - 4c1,2), respectively. The N5,4,3-regioisomeric structures were confirmed using 2D-NOESY (Nuclear Overhauser Effect Spectroscopy) and HMBC (Heteronuclear Multiple Bond Correlation) spectra. The antibacterial and antifungal activities of the synthesized compounds (2a - 2g, 4a - 5d) were evaluated in vitro against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin resistant S. aureus, Enterococcus faecalis and Candida albicans, Candida parapsilosis. Among the synthesized compounds, promising activities were observed with compounds 2g, 2h, 4a and 4b with lowest MIC values (4-8 µg/mL). The compounds 2i, 2j, 2k, 2l showed moderate activity. Additionally, a computational approach (ADMETlab 2.0) was used to evaluate the drug likeness properties of the compounds.

Hypophosphatemia related to the use of ibrutinib.

INTRODUCTION: Tyrosine kinase inhibitors (TKis) and Bruton's TKi (BTKis) constitute broadly used antitumor drug groups with almost completely tolerable and manageable side-effect profiles. Mainly side effects are cardiovascular and gastrointestinal for the TKi group. Hypophosphatemia is documented frequently in many studies with TKis but rarely mentioned with ibrutinib use up to the present. CASE REPORT: A 61-year-old patient with the diagnosis of chronic lymphocytic leukemia had hypophosphatemia-related complaints and symptoms when ibrutinib use was preferred for his second relapse of the disease. After drug discontinuation, we started ibrutinib again with an alternating dose. We managed to control hypophosphatemia, and the patient has been following up for 2 years in remission status without any support or a second drug need. MANAGEMENT AND OUTCOME: We have presented here a chronic lymphocytic leukemia case that developed mild-severe hypophosphatemia associated with ibrutinib use. By using an alternating dose of ibrutinib, we managed to control the disease and drug side effects. DISCUSSION: TKis and BTKis are widely in use for different indications. Hypophosphatemia is rare but it can cause drug discontinuation or change if it is not manageable. It is mentioned that hypophosphatemia can be seen due to a common group effect with the mechanism of causing secondary hyperparathyroidism and renal tubulopathy. In our case, we could explain the side effect of hypophosphatemia with secondary hyperparathyroidism and renal tubulopathy. Prospective, large-group studies are needed to explain the hypophosphatemia and other side effects of ibrutinib and new BTKis in detail.

A single-center experience of haploidentical stem cell transplantation in hematological malignancies.

BACKGROUND: Since well-designed prospective comparative trials are lacking, haploidentical hematopoietic stem cell transplantations approach should be based on the expertise of a particular center. In this study, we aimed to report the results and outcomes of patients who underwent haploidentical hematopoietic stem cell transplantation. METHODS: : Thirty-nine patients who underwent transplantation in our clinic between 2015 and 2022 were retrospectively analyzed. Primary end point of this study is to find out the survival rates of the patients. RESULTS: The overall survival of patients was 29.9 ± 4.9 months. The disease-free survival of the patients was 37.8 ± 5.7 months. The 3-year overall survival rate of the patients was %50 and the 3-year disease-free survival rate of the patients was %53. Nineteen patients were nonsurvivors among a total of 39 patients. Busulfan-fludarabine-thiotepa was the most frequently used conditioning regimen for transplantation. Busulfan-fludarabin-antithymocyte globulin regimen is the second preferred conditioning regimen. Cyclosporine- cyclophosphamide-mycophenolate mofetil was the most widely used graft-versus-host disease prophylaxis regimen. Sixteen patients had graft-versus-host disease, 28% of the patients had acute graft-versus-host disease, and 13% had chronic graft-versus-host disease. Gastrointestinal system consists of the most involved organs in graft-versus-host disease since 15% of the patients had gastrointestinal graft-versus-host disease. First-degree relatives (parent/child) were the most frequent donor source for haploidentical hematopoietic stem cell transplantation. Sepsis was the most frequent reason of death among transplant patients. DISCUSSION: In our center, we prefer to use high dose posttransplantation cyclophosphamide after haploidentical hematopoietic stem cell transplantation for graft-versus-host disease prophylaxis. With this approach, our center's overall survival and disease-free survival rates are comparable and compatible with the literature findings.

Asymptomatic unilateral phrenic nerve palsy after bortezomib treatment in a newly diagnosed multiple myeloma patient.

INTRODUCTION: Bortezomib is the first chemotherapeutic agent of proteosome inhibitor class that can be used in newly diagnosed and relapsed/refractory multiple myeloma. It is well known that bortezomib has side effects such as peripheral sensory, motor, or autonomic neuropathy. In this paper, we will present our patient who developed unilateral phrenic nerve palsy as an autonomic neuropathy after six cycles of subcutaneous bortezomib treatment. This case differs from other cases in that our patient was asymptomatic. CASE REPORT: A 57-year-old male patient was admitted with back pain and gait disturbances. In the thorax computed tomography, a soft tissue mass causing compression on the spinal canal was observed in the T12 vertebra. Bone biopsy pathology report resulted in diffuse plasma cell infiltration. The patient was diagnosed with stage ISS-3, IgG kappa type multiple myeloma. MANAGEMENT AND OUTCOME: Subcutaneous bortezomib 1 × 2.2 mg (Days 1-4-8-11) + intravenous cyclophosphamide 1000 mg (Day 1) + intravenous dexamethasone 40 mg (Days 1-2-3-4) (VCD chemotherapy protocol) was started. Totally six cycles of VCD were administered. While the patient did not have any respiratory symptoms, an elevation consistent with phrenic nerve palsy was observed in the left hemidiaphragm in the thorax computed tomography that was taken during the preparation for autologous hematopoietic stem cell transplantation. DISCUSSION: Bortezomib is a frequently used chemotherapeutic agent in patients with multiple myeloma and care should be taken in terms of the risk of developing phrenic nerve palsy in patients. There are cases of autonomic neuropathy developing after bortezomib treatment.

Comment on Zamfir et al. Hematologic Malignancies Diagnosed in the Context of the mRNA COVID-19 Vaccination Campaign: A Report of Two Cases. Medicina 2022, 58, 874.

The SARS-CoV-2 spike protein mRNA-based vaccines have prevented countless mortality and morbidity, and have an excellent risk/benefit ratio. However, various adverse events may rarely occur after the BNT162b2 vaccine, like any other medical intervention. The COVID-19 itself and the spike protein produced endogenously by mRNA vaccines may have immunological, microenvironmental, prothrombotic, and neoplastic effects. As a contribution to the published report, we would like to share our experience regarding four cases in which myeloid neoplasms emerged following the vaccination. Conclusions: There is no doubt that vaccination could continue along the lines of established universal recommendations. Meanwhile, all hematological adverse events must be closely monitored and reported. Further efforts should be focused on the probable pathobiological mechanisms and causalities of spike protein-related toxicity and clonal myeloid disorders.

Efficacy of eltrombopag in thrombocytopenia after hematopoietic stem celltransplantation.

BACKGROUND: Thrombocytopenia is a common complication following hematopoietic stem cell transplantation (HSCT). Eltrombopag has been used in thrombocytopenia treatment after HSCT in recent years. Herein, we present our experience of 25 patients treated with eltrombopag for post-HSCT thrombocytopenia. METHODS: Fifteen autologous hematopoietic stem cell transplantation (AHSCT) and 10 allogenic hematopoietic stem cell transplantation (allo-HSCT) recipients treated with eltrombopag for treatment of prolonged isolated thrombocytopenia (PIT) or secondary failure of platelet recovery (SFPR) in the stem cell transplantation unit of Hacettepe University Hematology Department between 2017 and 2021 were included in the study. The primary endpoint of this study is eltrombopag response in patients diagnosed with PIT or SFPR. Platelet count above 50,000/mm3 for five consecutive days without platelet transfusion was considered as eltrombopag response. Overall survival (OS) analyses were calculated based on the time between HSCT and death from any cause. The patients who were alive at the last follow-up were censored at this time for calculation of OS analyses. RESULTS: AHSCT (66.7% (10/15)) and allo-HSCT (50% (5/10)) recipients responded to eltrombopag for the treatment of post-HSCT thrombocytopenia. There was no excess toxicity related to the eltrombopag use. The median response duration of allo-HSCT recipients and AHSCT recipients were 41 (13-104) days and 50 (7-342) days, respectively. There was a statistically significant OS duration difference between the responders and nonresponders in allo-HSCT and AHSCT recipients with p values of 0.005 and 0.02, respectively. DISCUSSION: Eltrombopag is promising for the treatment of thrombocytopenia after AHSCT and allo-HSCT in terms of efficacy and safety.

Hepatitis E Virus Prevalence and Associated Risk Factors in High-Risk Groups: A Cross-Sectional Study.

BACKGROUND: Seroepidemiology, risk factors to hepatitis E virus exposure, and prevalence of hepatitis E virus viremia have not yet been investigated among patients under immunosuppression or with liver disease that are high risk for infection in Turkey. METHODS: In this cross-sectional study, 292 consecutive serum samples from renal transplant recipients, allogeneic hematopoietic stem cell transplant recipients, patients with acute hepatitis, and patients with chronic hepatitis C were prospectively collected in a ter- tiary university hospital. Sera were tested for hepatitis E virus immunoglobulin G/immunoglobulin M and hepatitis E virus ribonucleic acid using commercial enzyme-linked immunosorbent assay and in-house nested polymerase chain reaction with Sanger sequencing, respectively. Sociodemographic, clinical, laboratory data, and risk factors were collected using a questionnaire and hospital database. Multiple logistic regression analysis was employed to identify independent predictors for anti-hepatitis E virus seropositivity. RESULTS: Among all patients, only 2 patients (1 renal transplant recipient and 1 patient with acute hepatitis) were identified as having hepatitis E virus genotype 3 viremia. Hepatitis E virus viremia rate was 0.6% in whole group. These patients showed no signs of chronic hepatitis E virus infection for 6 months and were spontaneously seroconverted 6 months after enrollment. Anti-hepatitis E virus IgG was positive in 29 patients yielding a hepatitis E virus seroprevalence of 9.9%. Older age (adjusted odds ratio: 1.03, 95% CI, 1.00-1.06; P = .022) and eating undercooked meat (adjusted odds ratio: 3.11, 95% CI, 1.08-8.92; P = .034) were independent risk factors to anti- hepatitis E virus seropositivity in all patients. Similarly, multiple logistic regression analysis demonstrated that age (adjusted odds ratio: 1.03, 95% CI, 0.99-1.07, P = .058) and eating undercooked meat (adjusted odds ratio: 5.77, 95% CI, 1.49-22.25, P = .011) were indepen- dent risk factors for anti-hepatitis E virus IgG positivity in the liver disease subgroup consisting of acute hepatitis and chronic hepatitis C patients. CONCLUSION: The hepatitis E virus seroprevalence rate was high (9.9%), despite low viremia rate (0.6%) in high-risk patients. The emer- gence of hepatitis E virus genotype 3 might indicate a serious problem for these patients. Future investigations are needed to elucidate foodborne transmission routes of hepatitis E virus in Turkey.