Expanding the Role of Boron in New Drug Chemotypes: Properties, Chemistry, Pharmaceutical Potential of Hemiboronic Naphthoids.

New chemotypes and bioisosteres can open a new chemical space in drug discovery and help meet an urgent demand for novel agents to fight infections and other diseases. With the aim of identifying new boron-containing drug chemotypes, this article details a comprehensive evaluation of the pseudoaromatic hemiboronic naphthoids, benzoxaza- and benzodiazaborines. Relevant physical properties in aqueous media (acidity, solubility, log P, and stability) of prototypic members of four subclasses were determined. Both scaffolds are amenable to common reactions used in drug discovery, such as chemoselective Suzuki-Miyaura, Chan-Lam, and amidation reactions. Small model libraries were prepared to assess the scope of these transformations, and the entire collection was screened for antifungal (Candida albicans) and antibacterial activity (MRSA, Escherichia coli), unveiling promising benzoxazaborines with low micromolar minimum inhibitory concentration values. Select DMPK assays of representative compounds suggest promising drug-like behavior for all four subclasses. Moreover, several drug isosteres were evaluated for anti-inflammatory and anticancer activity as appropriate.

Autologous stem cell transplantation for multiple myeloma patients with chronic kidney disease: a safe and effective option.

Chronic Kidney Disease (CKD) is a frequent complication in patients with multiple myeloma (MM) and is associated with adverse outcomes. The use of autologous stem cell transplantation (ASCT) has improved disease outcomes, however, the safety and efficacy of ASCT in patients with CKD has been the subject of debate. To investigate this, we conducted a retrospective analysis of 370 MM patients who underwent their first ASCT, including those with mild, moderate and severe CKD as well as normal renal function at the time of transplant. No significant difference in ASCT-related mortality, Progression-Free or Overall Survival was noted between the different renal function groups. A decline in estimated glomerular filtration rate (eGFR) at 1-year of >8.79% was associated with poorer overall survival (p < 0.001). The results of this study show that ASCT is a safe and effective option for myeloma patients with CKD, including those on dialysis. Patients who demonstrate renal deterioration at 1-year post-transplant should be closely monitored as this is a predictor for poor survival.

Structure-activity relationship and bioactivity studies of neurotrophic trans-banglene.

The synthesis and bioactivity of neurotrophic banglenes and derivatives is described, establishing a structure-activity relationship which enables future mechanistic studies. Neuritogenesis assays indicate that (-) trans-banglene is the active enantiomer. Assays performed with and without NGF protein suggest that neurotrophic activity and potentiation of NGF activity by (-) trans-banglene might be distinct unassociated processes. Interestingly, (-) trans-banglene potentiation of NGF-induced neuritogenesis is unaffected by the presence of Erk1/2, Akt and Pkc inhibitors.

Lewis or Brønsted? A Rectification of the Acidic and Aromatic Nature of Boranol-Containing Naphthoid Heterocycles.

Boron-containing heterocycles are important in a variety of applications from drug discovery to materials science; therefore a clear understanding of their structure and reactivity is desirable to optimize these functions. Although the boranol (B-OH) unit of boronic acids behaves as a Lewis acid to form a tetravalent trihydroxyborate conjugate base, it has been proposed that pseudoaromatic hemiboronic acids may possess sufficient aromatic character to act as Brønsted acids and form a boron oxy conjugate base, thereby avoiding the disruption of ring aromaticity that would occur with a tetravalent boronate anion. Until now no firm evidence existed to ascertain the structure of the conjugate base and the aromatic character of the boron-containing ring of hemiboronic "naphthoid" isosteres. Here, these questions are addressed with a combination of experimental, spectroscopic, X-ray crystallographic, and computational studies of a series of model benzoxazaborine and benzodiazaborine naphthoids. Although these hemiboronic heterocycles are unambiguously shown to behave as Lewis acids in aqueous solutions, boraza derivatives possess partial aromaticity provided their nitrogen lone electron pair is sufficiently available to participate in extended delocalization. As demonstrated by dynamic exchange and crossover experiments, these heterocycles are stable in neutral aqueous medium, and their measured pKa values are consistent with the ability of the endocyclic heteroatom substituent to stabilize a partial negative charge in the conjugate base. Altogether, this study corrects previous inaccuracies and provides conclusions regarding the properties of these compounds that are important toward the methodical application of hemiboronic and other boron heterocycles in catalysis, bioconjugation, and medicinal chemistry.

ABVD and BEACOPP regimens’ effects on fertility in young males with Hodgkin lymphoma

Purpose Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. Methods The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. Results Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. Conclusions ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP’s effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy (AU)

ABVD and BEACOPP regimens' effects on fertility in young males with Hodgkin lymphoma.

PURPOSE: Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. METHODS: The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. RESULTS: Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. CONCLUSIONS: ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.

SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking.

Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune 'resetting'. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.

Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis.

BACKGROUND: Although autologous stem cell transplantation (ASCT) may achieve disease control in severe treatment-resistant Crohn's disease (CD), relapse is frequent, and there is little information regarding long-term outcomes in terms of response to subsequent treatments and complications of ASCT. DESIGN: Retrospective evaluation of UK patients treated on a compassionate basis from three UK tertiary centres. METHODS: We summarize long-term outcomes of six previously unreported patients with severe treatment-resistant CD treated with ASCT according to international guidelines between 2003 and 2009. Median duration of CD before ASCT was 14 (7-22) years. Following stem cell mobilization, patients were treated with high-dose cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (7.5 mg/kg) followed by ASCT. RESULTS: All patients tolerated ASCT with routine toxicities and no treatment-related mortality and are alive at 50-123 months post-ASCT. Clinical and endoscopic remissions of CD were confirmed at 3 months post-ASCT in five patients, although median time to next treatment for inflammatory disease was 10 months (range: 3-16 months). Subsequently, disease control was achieved with previously ineffective and newer treatments, with surgery performed predominantly for pre-existing fibrotic strictures. Two patients became independent of home total parenteral nutrition (TPN). Reported late complications of ASCT included hypothyroidism and ovarian failure. CONCLUSION: Long-term follow-up supports the safety and feasibility of ASCT as a means of achieving short-term control of severe CD whilst potentially re-sensitizing the disease to medical therapy and reducing requirements for surgery and TPN. Given the inevitability of relapse, pre-emptive salvage and/or maintenance treatments post-ASCT should be the focus of future trials.

Intraspecific and intragenomic variability of ITS rDNA sequences reveals taxonomic problems in Ceratocystis fimbriata sensu stricto.

Fourteen new species in the Latin American Clade (LAC) of the Ceratocystis fimbriata complex recently were distinguished from C. fimbriata sensu stricto largely based on variation in ITS rDNA sequences. Among the 116 isolates representing the LAC, there were 41 ITS haplotypes. Maximum parsimony (MP) analysis of ITS sequences produced poorly resolved trees. In contrast, analyses of mating-type genes (MAT1-1-2 and MAT1-2-1) resolved a single MP tree with branches of high bootstrap and posterior probability support. Four isolates showed intragenomic variation in ITS sequences. Cloning and sequencing of PCR products from a single haploid strain identified two or more ITS sequences differing at up to 16 base positions and representing two described species. Isolates from introduced populations that appeared to be clonal based on microsatellite markers varied at up to 14 bp in ITS sequence. Strains of seven Brazilian ITS haplotypes and an isolate from Ipomoea batatas (on which the species name C. fimbriata was based) were fully interfertile in sexual crosses. These analyses support three phylogenetic species that differ in pathogenicity: C. platani, C. cacaofunesta and C. colombiana. Five ITS species (C. manginecans, C. mangicola, C. mangivora, C. acaciivora, C. eucalypticola) appear to be ITS haplotypes that have been moved from or within Brazil on nursery stock. The taxonomic status of other species delineated primarily by ITS sequences (C. diversiconidia, C. papillata, C. neglecta, C. ecuadoriana, C. fimbriatomima, C. curvata) needs further study, but they are considered doubtful species.

Hematopoietic stem cell transplantation in T-prolymphocytic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation and the Royal Marsden Consortium.

T-prolymphocytic leukemia (T-PLL) has a very poor prognosis with conventional immunochemotherapy. Incidental reports suggest that allogeneic hematopoietic stem cell transplantation (allo-HSCT) might have a role in this disease. Therefore, the purpose of the present study was to analyze the outcome of transplants for T-PLL registered with the European Group for Blood and Marrow Transplantation database and the Royal Marsden Consortium. Eligible were 41 patients with a median age of 51 (24-71) years; median time from diagnosis to treatment was 12 months, and in complete remission (CR) (11), partial remission (PR) (12), stable or progressive disease (13) and unknown in 5 patients. A total of 13 patients (31%) received reduced-intensity conditioning. Donors were HLA-identical siblings in 21 patients, matched unrelated donors in 20 patients. With a median follow-up of surviving patients of 36 months, 3-year relapse-free survival (RFS) and OS was 19% (95% CI, 6-31%) and 21% (95% CI, 7-34%), respectively. Multivariate analysis identified TBI and a short interval between diagnosis and HSCT as factors associated with favorable RFS. Three-year non relapse mortality and relapse incidence were each 41% with the majority of relapses occurring within the first year. These data indicate that allo-HSCT may provide effective disease control in selected patients with T-PLL.

Chronic inflammatory demyelinating polyradiculoneuropathy: a role for haematopoietic stem cell transplantation?

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical syndrome of a chronic progressive or relapsing and remitting, symmetrical, sensory and motor radiculoneuropathy. The immune reaction in CIDP is characterised by selective inflammation of peripheral nerves and is probably due to the interaction of cellular and humoral responses. Only three treatments for CIDP have demonstrated benefit in randomised studies, corticosteroids, plasma exchange and intravenous immunoglobulin. 25% of patients fail to respond or do not respond adequately to these treatments. Experimental data in animal models have shown that several autoimmune disorders, either congenital or acquired, can be transferred and/or treated by the transplantation of bone marrow stem cells. Haematopoietic stem cell transplantation (HSCT) has been performed with varying success in over 700 patients with autoimmune disorders throughout Europe. The experience in CIDP is very limited. This article will review current understanding of CIDP and experience of the use of HSCT in refractory CIDP.

Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant.

Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.

Thalidomide induced remission of refractory diffuse large B-Cell Lymphoma post-allogeneic SCT.

Patients who relapse after High dose therapy and autologous stem cell transplant (ASCT) for Diffuse large B cell Lymphoma (DLBCL) have a poor prognosis with a median survival of only 3-6 month.1-2 This case demonstrates the ability of thalidomide at low doses to induce durable response in a patient with DLBCL who relapsed after full intensity allogeneic transplantation.

Second autologous transplant with cyclosporin/interferon alpha-induced graft versus host disease for patients who have failed first-line consolidation.

The prognosis for patients with non-Hodgkin's lymphoma (NHL) and advanced Hodgkin's disease (HD) who relapse following autologous transplant is poor. We report on a pilot study designed to evaluate the feasibility of using Cyclosporin A and interferon alpha to induce autologous GVHD following a second autologous transplant for relapsed lymphoma. In all, 10 patients entered the study with median age 46.5 years. Diagnosis was NHL (n=7) or Hodgkin's lymphoma (n=3). All had relapsed from a prior autologous transplant. The second transplant was well tolerated by all patients. Histological changes consistent with cutaneous GVHD developed in 30% of patients at a median of 22.5 days from transplant and settled spontaneously in all cases. Five patients have died (four from progressive disease) at a median 7 months from second transplant. Five patients are still alive and in complete remission at a median of 20 months from transplant. Median overall survival for the group is 13.5 months and median relapse-free survival has not been reached at 42 months. This is a well-tolerated regimen for use in this poor-risk group of patients with lymphoma. The overall survival and event-free survival are encouraging, however further studies are necessary.

The effects of prior induction therapy with melphalan on subsequent peripheral blood progenitor cell transplantation for myeloma.

High dose chemoradiotherapy with autologous peripheral blood progenitor cell transplantation (PBPCT) may improve outcome in myeloma. Melphalan is an effective drug in the treatment of myeloma, but is potentially toxic to progenitor cells. We studied 8 patients receiving intermittent intravenous melphalan (25 mg/m2) as induction therapy before PBPCT to assess engraftment characteristics post-transplantation. Comparison was made with an age-matched control group of patients with non-Hodgkins lymphoma who had not received melphalan during induction therapy. There was correlation (P=0.037) between the dose of melphalan per kg body weight given, premobilization, and days to neutrophil engraftment, but no significant difference between the two groups in neutrophil recovery. The study group had delayed platelet recovery (P=0.01) and required more platelet support post-transplantation (P=0.05). 3-4 weekly melphalan (25 mg/m2) up to 6 courses was delivered to patients who went on to PBPCT without significantly influencing neutrophil recovery but with a negative impact on platelet recovery.

Selective reconstitution of human D4 dopamine receptor variants with Gi alpha subtypes.

G protein-coupled receptors (GPCRs) are seven-transmembrane (TM) helical proteins that bind extracellular molecules and transduce signals by coupling to heterotrimeric G proteins in the cytoplasm. The human D4 dopamine receptor is a particularly interesting GPCR because the polypeptide loop linking TM helices 5 and 6 (loop i3) may contain from 2 to 10 similar direct hexadecapeptide repeats. The precise role of loop i3 in D4 receptor function is not known. To clarify the role of loop i3 in G protein coupling, we constructed synthetic genes for the three main D4 receptor variants. D4-2, D4-4, and D4-7 receptors contain 2, 4, and 7 imperfect hexadecapeptide repeats in loop i3, respectively. We expressed and characterized the synthetic genes and found no significant effect of the D4 receptor polymorphisms on antagonist or agonist binding. We developed a cell-based assay where activated D4 receptors coupled to a Pertussis toxin-sensitive pathway to increase intracellular calcium concentration. Studies using receptor mutants showed that the regions of loop i3 near TM helices 5 and 6 were required for G protein coupling. The hexadecapeptide repeats were not required for G protein-mediated calcium flux. Cell membranes containing expressed D4 receptors and receptor mutants were reconstituted with purified recombinant G protein alpha subunits. The results show that each D4 receptor variant is capable of coupling to several G(i)alpha subtypes. Furthermore, there is no evidence of any quantitative difference in G protein coupling related to the number of hexadecapeptide repeats in loop i3. Thus, loop i3 is required for D4 receptors to activate G proteins. However, the polymorphic region of the loop does not appear to affect the specificity or efficiency of G(i)alpha coupling.

Possible mechanism of selective inotropic activity of the n-butanolic fraction from Berberis aristata fruit.

Berberis aristata is an edible plant employed in South Asian traditional medicine; in particular, its fruit is used as a tonic remedy for liver and heart. In isolated cardiac tissues, Berberis aristata fruit extract exhibits a positive inotropic action. Activity-directed fractionation using organic solvents revealed that the cardiotonic activity is concentrated in the n-butanolic fraction (BF). The cardiac action of BF was investigated in spontaneously beating right atria and in electrically driven right ventricular strips and left atria obtained from reserpinized guinea pigs. The results show that this fraction produces a dose-dependent positive inotropic action with little effect on heart rate. To study its possible mode of action, guinea pig atria were pretreated with propranolol, a beta-adrenoceptor blocking agent. This treatment abolished the cardiotonic effect of isoprenaline, whereas the cardiotonic effect of BF remained unaltered, suggesting that this effect does not involve stimulation of beta-adrenoceptors. On the other hand, application of carbachol reverses only part of the BF-induced increase in ventricular force of contraction, indicating that besides a cyclic AMP (cAMP)-dependent mechanism, a cAMP-independent mechanism underlies the inotropic action of BF. This is in line with the observation that the dynamics of isometric twitch contractions are not significantly altered by BF. Investigations in skinned myocardial preparations showed that BF modulates the calcium-dependent interaction of actin and myosin, apparently by reducing the cooperativity of the calcium-dependent binding of myosin to actin, i.e., there is enhanced calcium activation at low to physiological intracellular calcium, and reduced calcium activation at high intracellular calcium concentrations as present, for example, in ischemic calcium overload. These data indicate that the edible plant, Berberis aristata, contains active principle(s) that cause(s) a selective inotropic effect, involving-in the form of the modulatory effect on actin myosin cooperativity-a novel mechanism of action. Further phytochemical and pharmacological studies may lead to isolation and structural identification of an attractive, new cardiotonic agent from Berberis aristata fruit.