Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D (Calcitriol): Refinement of the Side Chain.

Current efforts in the vitamin D field are directed toward the development of highly antiproliferative yet noncalcemic analogues of the natural hormone 1α,25-dihydroxyvitamin D (1,25D). We have recently reported the design, synthesis, biological evaluation, and crystal structures of a series of novel analogues that both lack the steroidal C-ring and have an -phenylene ring replacing the steroidal cyclopentane D-ring. We have now investigated the potentiating effects of incorporating selected modifications (hexafluorination and/or an internal triple bond) within the steroidal side chain in our series.

The self-association equilibrium of DNAJA2 regulates its interaction with unfolded substrate proteins and with Hsc70.

J-domain proteins tune the specificity of Hsp70s, engaging them in precise functions. Despite their essential role, the structure and function of many J-domain proteins remain largely unknown. We explore human DNAJA2, finding that it reversibly forms highly-ordered, tubular structures that can be dissociated by Hsc70, the constitutively expressed Hsp70 isoform.

The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands.

Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than calcitriol. This structural review covers VDR ligands published to date.

Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D.

The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D (1,25D, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D that lack the C-ring and possess an -phenylene ring that replaces the natural D-ring. The new analogues (, ) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system.

Ustekinumab and vedolizumab for the prevention of postoperative recurrence of Crohn's disease: Results from the ENEIDA registry.

Background: Anti-TNF agents are the only effective biological agents for the prevention of postoperative recurrence (POR) in Crohn's disease (CD). However, they are contraindicated or have been shown to fail in some patients. Although ustekinumab and vedolizumab were licensed for CD some years ago, data in this setting are scarce.

Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D Analogs with Locked Mobility at C-17.

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility.

Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico/In Vitro Screening Methods.

The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. To this end a multi-target virtual screening approach focused on host-based targets related to viral entry, followed by the experimental evaluation of the antiviral activity of selected compounds, has been carried out.

COVID-19: Drug Targets and Potential Treatments.

Currently, humans are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which threatens public health worldwide. To date, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. In this paper, we will focus on the main virus-based and host-based targets that can guide efforts in medicinal chemistry to discover new drugs for this devastating disease.

Innovative Three-Step Microwave-Promoted Synthesis of -Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation.

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production.

Synthesis of 28,28,28-trideutero-25-hydroxydihydrotachysterol.

As part of our program on synthesis of labeled vitamin D metabolites and analogs, we describe here an efficient and versatile synthetic approach to 28,28,28-trideutero- 25-hydroxydihydrotachysterol where isotopic labeling was incorporated stereoselectively in the last step of the synthesis. This deuterated compound will allow the study this analog in vitro or in vivo and to measure AT10-like compounds in serum by LC-MS/MS.

Total synthesis of 1α,25-dihydroxyvitamin D analogs modified at the side chain and D-ring.

Herein, we describe a synthetic strategy to access 1α,25-dihydroxyvitamin D3 (calcitriol) analogs with natural or unnatural configuration at C20 and unsaturation at the D-ring. The synthetic approach is exemplified by the synthesis of two potent analogs, namely 1α,25-dihydroxy-16-en-23-yne-vitamin D3 and 1α,25-dihydroxy-20-epi-24a-homo-26,27-dimethyl-vitamin D3. A key feature of the synthetic strategy is the generation of an unnatural configuration at C20 by a catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with the CuH species in a micellar system.

Aromatic-Based Design of Highly Active and Noncalcemic Vitamin D Receptor Agonists.

We report the design, synthesis, biological evaluation, and structural analysis of a new class of vitamin D analogues that possess an aromatic m-phenylene D-ring and an alkyl chain replacing the C-ring. A key feature of the synthetic strategy is a stereoselective Pd-catalyzed construction of the triene system in aqueous medium that allows the rapid preparation of small amounts of VDR ligands for biological screening. Analogues with the shorter (2a) and longer (2d, 2e) side chains attached to the triene system have no calcemic activity.

Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.

Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study.

Synthesis of Side-Chain Locked Analogs of 1α,25-Dihydroxyvitamin D Bearing a C17 Methyl Group.

A convergent synthesis of side-chain locked vitamin D analogs 3 and 4, which bind strongly in silico to the vitamin D receptor (VDR), is described. The synthetic approach features an S2'- syn displacement of carbamates by cuprates to set the challenging quaternary stereogenic center at C17 and a Pd-catalyzed construction of the triene system in the presence of a diyne moiety.

Stereoselective Palladium-Catalyzed Approach to Vitamin D Derivatives in Protic Medium.

We describe an efficient convergent synthesis of vitamin D metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D and 3-epi-vitamin D metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies.

Stereoselective synthesis of 25S,26-dihydroxyvitamin D.

A convergent approach to 25S,26-dihydroxyvitamin D (1) has been developed in our laboratories. The A-ring and the CD-fragment are constructed from ergocalciferol and Inhoffen-Lythgoe diol, respectively. The triene system is assembled by a Wittig-Horner coupling.

Total synthesis of 1α,25-dihydroxyvitamin D (calcitriol) through a Si-assisted allylic substitution.

Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted S2'-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson-Khand cyclization to form the CD-ring skeleton.

Vitamin D receptor 2016: novel ligands and structural insights.

Vitamin D activates via its hormonal form 1α,25-dihydroxyvitamin D (1α,25(OH)D), the transcription factor vitamin D receptor (VDR). VDR is expressed in most human tissues and has more than 1,000 target genes. Thus, 1α,25(OH)D and its synthetic analogs have a broad physiological impact.

A new approach to 19-nor-A-ring phosphine oxide for the convergent synthesis of 19-nor-calcitriol.

A new approach to 19-nor-A-ring phosphine oxide 5 together with a convergent synthesis of the vitamin D analogue 1α,25-dihydroxy-19-norvitamin D (3) have been developed. The 19-nor-A-ring is constructed from (S)-carvone. The triene system is assembled by a Wittig-Horner coupling.

Carborane-based design of a potent vitamin D receptor agonist.

The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D (1,25D) and an -carborane (dicarba--1,2-dodecaborane) at the end of its side chain.

Stereoselective synthesis of 1β,25-Dihydroxyvitamin D and its 26,27-hexadeuterated derivative.

A mild convergent synthesis of 1β,25-dihydroxyvitamin D (3a), a metabolite of vitamin D, and its C26,27-hexadeuterated derivative (3b) are described. The A-ring and the CD-fragments are constructed from (R)-carvone and Inhoffen-Lythgoe diol, respectively. The triene system is assembled by a Pd(0)-catalyzed process, which involves an enol-triflate (A-ring fragment) and an alkenyl boronate (CD-side chain fragment).

Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment.

The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown. We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents.

PET/MRI and PET/MRI/SISCOM coregistration in the presurgical evaluation of refractory focal epilepsy.

We aimed to investigate the usefulness of coregistration of positron emission tomography (PET) and magnetic resonance imaging (MRI) findings (PET/MRI) and of coregistration of PET/MRI with subtraction ictal single-photon emission computed tomography (SPECT) coregistered to MRI (SISCOM) (PET/MRI/SISCOM) in localizing the potential epileptogenic zone in patients with drug-resistant epilepsy. We prospectively included 35 consecutive patients with refractory focal epilepsy whose presurgical evaluation included a PET study. Separately acquired PET and structural MRI images were coregistered for each patient.