Synthesis of bioconjugate sesterterpenoids with phospholipids and polyunsaturated fatty acids

A series of sesterterpenoid bioconjugates with phospholipids and polyunsaturated fatty acids (PUFAs) have been synthesized for biological activity testing as antiproliferative agents in several cancer cell lines. Different substitution analogues of the original lipidic ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) are obtained varying the sesterterpenoid in position 1 or 2 of the glycerol or a phosphocholine or PUFA unit in position 3. Simple bioconjugates of sesterterpenoids and eicosapentaenoic acid (EPA) have been obtained too. All synthetic derivatives were tested against the human tumour cell lines HeLa (cervix) and MCF-7 (breast). Some compounds showed good IC50 (0.3 and 0.2 μM) values against these cell lines.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-30518 and SAF2014-59716-R). Junta de Castilla y León BIO/SA59/15.Peer reviewe

Halimanes and cancer: ent-halimic acid as a starting material for the synthesis of antitumor drugs

The development of new anti-cancer agents is an urgent necessity nowadays, as it is one of the major causes of mortality worldwide. Many drugs currently used are derived from natural products. Halimanes are a class of bicyclic diterpenoids present in various plants and microorganisms. Many of them exhibit biological activities such as antitumor, antimicrobial, or anti-inflammatory. Among them, ent-halimic acid is an easily accessible compound, in large quantities, from the ethyl acetate extract of the plant Halimium viscosum, and it has been used as a starting material in a number of bioactive molecules. In this work, we review all the natural halimanes with antitumor and related activities until date as well as the synthesis of antitumor compounds using ent-halimic acid as a starting material

Beta cell functionality and hepatic insulin resistance are major contributors to type 2 diabetes remission and starting pharmacological therapy: from CORDIOPREV randomized controlled trial

In order to assess whether previous hepatic IR (Hepatic-IR fasting) and beta-cell functionality could modulate type 2 diabetes remission and the need for starting glucose- lowering treatment, newly-diagnosed type 2 diabetes participants who had never received glucose-lowering treatment (190 out of 1002) from the CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (a prospective, randomized and controlled clinical trial), were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was defined according to the American Diabetes Association recommendation for levels of HbA1c, fasting plasma glucose and 2h plasma glucose after oral glucose tolerance test, and having maintained them for at least 2 consecutive years. Patients were classified according to the median of Hepatic-IR fasting and beta-cell functionality, measured as the disposition index (DI) at baseline. Cox proportional hazards regression determined the potential for Hepatic-IR fasting and DI indexes as predictors of diabetes remission and the probability of starting pharmacological treatment after a 5-year follow-up. Low-Hepatic-IR fasting or high-DI patients had a higher probability of diabetes remission than high-Hepatic-IR fasting or low-DI subjects (HR:1.79; 95% CI 1.06_3.05; and HR:2.66; 95% CI 1.60_4.43, respectively) after a dietary intervention with no pharmacological treatment and no weight loss. The combination of low- Hepatic-IR fasting and high-DI presented the highest probability of remission (HR:4.63; 95% CI 2.00_10.70). Among patients maintaining diabetes, those with high- Hepatic-IR fasting and low-DI showed the highest risk of starting glucose-lowerin

Factors associated with the humoral response after three doses of COVID-19 vaccination in kidney transplant recipients

[Introduction] Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients.[Methods] To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response.[Results] Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses.[Discussion] In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.This study was supported by a grant from the Fondo de Investigación Sanitaria (FIS/PI21/00357), which is co-founded by Fondos Europeos para el Desarrollo Regional (FEDER) “Una manera de hacer Europa”. VG-R, IO-M and AB-R were supported by Instituto de Salud Carlos III (CD19/00143, FI19/00298 and CM19/00051, respectively). MP-B was supported by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades [DOC_01646 to MP-B] and YP was supported by the Consejería de Salud y Familias of Junta de Andalucía through the “Nicolás Monardes” [RC-0006-2021].Peer reviewe

2-oxa y 6-oxanortropanos: productos naturales, síntesis y actividades biológicas

Tropane core is found in many natural compounds as Solanaceae alkaloids, atropine or scopolamine. In relation with this skeleton, nor-tropane core appears in calystegines, which are polyhydroxylated alkaloids isolated from rhizomes of plants as Calystegia sepium or Convolvulus arvensis. These compounds show an important glucosidase-inhibitory activity, inhibiting β-glucosidase and α-galactosidase among others. These enzymes are altered in diverse metabolic pathologies as the Gaucher’s disease. Synthesis of oxygenated analogues of these compounds are arising due to these pharmacological properties. In this review, 2-oxa- and 6-oxa-nortropanes last related researches are shown.El esqueleto de tropano se encuentra presente en compuestos naturales como los alcaloides de solanáceas atropina o escopolamina; relacionado con este esqueleto está el de nor-tropano presente en calisteginas, alcaloides polihidroxilados aislados de los rizomas de plantas como Calystegia sepium o Convolvulus arvensis que presentan una importante actividad inhibidora de glicosidasas como β-glucosidasa y α-galactosidasa entre otras. Estas enzimas están alteradas en diversas patologías relacionadas con el metabolismo de glúcidos como la enfermedad de Gaucher. Estas interesantes propiedades están haciendo que la síntesis de análogos oxigenados de nor-tropano esté despertando un gran interés. En esta publicación se recogen las últimas investigaciones sobre 2-oxa- y 6-oxa-nortropanos

Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes

Organocatalysis constitutes one of the main research areas in organic chemistry from the last two decades. This chemistry has been applied to the synthesis of many natural products and structures in a manner that reduces the residues and so the ecological impact. In this review, we consider the work that has been done for the synthesis of bicyclo[3.2.1]octane framework. This structure is present in many natural products with very important biological activities

Antibacterial Natural Halimanes: Potential Source of Novel Antibiofilm Agents

The development of new agents against bacteria is an urgent necessity for human beings. The structured colony of bacterial cells, called the biofilm, is used to defend themselves from biocide attacks. For this reason, it is necessary to know their structures, develop new agents to eliminate them and to develop new procedures that allow an early diagnosis, by using biomarkers. Among natural products, some derivatives of diterpenes with halimane skeleton show antibacterial activity. Some halimanes have been isolated from marine organisms, structurally related with halimanes isolated from Mycobacterium tuberculosis. These halimanes are being evaluated as virulence factors and as tuberculosis biomarkers, this disease being one of the major causes of mortality and morbidity. In this work, the antibacterial halimanes will be reviewed, with their structural characteristics, activities, sources and the synthesis known until now

Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development

The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in ¿2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected ¿2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.Spanish Ministry of Economy and Competitiveness (SAF2012-36566), Madrid Regional Government (Oncocycle S2011/BMD-2470), Instituto de Salud Carlos III (ACCI-CIBERER-16); financial support to MAP: RTICC SAF2008-03871 (MINECO). Spanish Association Against Cancer (AECC).Peer Reviewe

Synthesis of Bioconjugate Sesterterpenoids with Phospholipids and Polyunsaturated Fatty Acids

A series of sesterterpenoid bioconjugates with phospholipids and polyunsaturated fatty acids (PUFAs) have been synthesized for biological activity testing as antiproliferative agents in several cancer cell lines. Different substitution analogues of the original lipidic ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) are obtained varying the sesterterpenoid in position 1 or 2 of the glycerol or a phosphocholine or PUFA unit in position 3. Simple bioconjugates of sesterterpenoids and eicosapentaenoic acid (EPA) have been obtained too. All synthetic derivatives were tested against the human tumour cell lines HeLa (cervix) and MCF-7 (breast). Some compounds showed good IC50 (0.3 and 0.2 μM) values against these cell lines