Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC.

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC.

The ability of HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and ( S )-MCG-IV-210 sensitize HIV-1 infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, ( S )-MCG-IV-210 derivatives, based on the piperidine scaffold which engage the gp120 within the Phe43 cavity by targeting the highly-conserved Asp 368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp 368 , opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination HIV-1-infected cells.

Synthesis of and Metal Complexation with a Chiral Cyclam.

Tetraazamacrocycles, like cyclam 1, are well-studied polyamine ligands for metal ions that were first developed to model biological processes. Despite being studied for nearly 60 years, the development of chiral variants of 1 has been limited. We report the synthesis of a chiral variant of 1, the tetraazamacrocycle 2. Outlined herein are the synthesis of 2, a preliminary study of its complexation with metal ions, and the properties of the resulting metal complexes.

Synthesis and Applications of the C2-Symmetrical Diamine 2,7-Diazabicyclo[4.4.1]undecane.

Chiral diamines are particularly useful as ligands for asymmetric catalysis. In an effort to expand the library of such diamines, the synthesis and resolution of the C2-symmetric diamine 2,7-diazabicyclo[4.4.1]undecane [(-)-1] are reported. Diamine (-)-1 has been prepared in multigram quantities from the known bicyclic diketone 7 in four steps without the need for chromatographic purification. Derivatives of (-)-1, i.e., the bis-methylated diamine (+)-5 and two diastereomeric tricyclic analogs, were evaluated as potential sparteine surrogates. The solid-state structure of the (+)-5-methyllithium complex was obtained. High levels of asymmetric induction were observed while using (+)-5 as a ligand in palladium-mediated asymmetric allylations.

A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics.

Drugs used for the treatment of castration resistant prostate cancer (CRPC) include Abiraterone acetate (Zytiga®) and Enzalutamide (XTANDI®). However, these drugs provide clinical benefit in metastatic disease for only a brief period before drug resistance emerges. One mechanism of drug resistance involves the overexpression of type 5 17-ß-hydroxysteroid dehydrogenase (aldo-keto reductase 1C3 or AKR1C3), a major enzyme responsible for the formation of intratumoral androgens that activate the androgen receptor (AR). 3-((4-Nitronaphthalen-1-yl)amino)benzoic acid 1 is a "first-in-class" AKR1C3 competitive inhibitor and AR antagonist. Compound 1 was compared in a battery of in vitro studies with structurally related N-naphthyl-aminobenzoates, and AKR1C3 targeted therapeutics e.g. GTx-560 and ASP9521, as well as with R-bicalutamide, enzalutamide and abiraterone acetate. Compound 1 was the only naphthyl derivative that was a selective AKR1C3 inhibitor and AR antagonist in direct competitive binding assays and in AR driven reporter gene assays. GTx-560 displayed weak activity as a direct AR antagonist but had high potency in the AR reporter gene assay consistent with its ability to inhibit the co-activator function of AKR1C3. By contrast ASP9521 did not act as either an AR antagonist or block AR reporter gene activity. Compound 1 was the only compound that showed comparable potency to inhibit AKR1C3 and act as a direct AR antagonist. Compound 1 blocked the formation of testosterone in LNCaP-AKR1C3 cells, and the expression of PSA driven by the AKR1C3 substrate (4-androstene-3,17-dione) and by an AR agonist, 5α-dihydrotestosterone consistent with its bifunctional role. Compound 1 blocked the nuclear translocation of the AR at similar concentrations to enzalutamide and caused disappearance of the AR from cell lysates. R-biaclutamide and enzalutamide inhibited AKR1C3 at concentrations 200x greater than compound 1, suggesting that its bifunctionality can be explained by a shared pharmacophore that can be optimized.

Effectiveness of an osteoporosis intervention among older adults residing in assisted living facilities.

OBJECTIVES: To describe demographic and clinical risk factors for osteoporosis among persons aged 60 years and older residing in assisted living facilities and to compare the frequency of bone-mineral density (BMD) testing and initiation of pharmacotherapy for osteoporosis (prevention/treatment) in both a control and experimental cohort. DESIGN: Prospective cohort study. SETTING: Sixteen separate assisted living facilities from November 2001 through July 2002. PARTICIPANTS: Assisted living facility ambulatory residents (N = 111) aged 60 years and older. INTERVENTION: Based on the subject's risk factors for osteoporosis and FRACTURE Index score (female subjects only), written recommendations were made from a multidisciplinary team to increase the percentage of residents evaluated (via central dual-energy x-ray absorptiometry [DEXA] scan) and/or treated for osteoporosis. MAIN OUTCOME MEASURES: FRACTURE Index was calculated on all female participants and reported with BMD or without BMD results by convention. An investigator-developed osteoporosis risk-factor assessment questionnaire was used to evaluate risk factors present for each participant. Numbers of subjects being evaluated for osteoporosis via DEXA scan and numbers of subjects having pharmacotherapy altered to prevent or treat osteoporosis were recorded. RESULTS: One hundred eleven older adults (average age 84 [range 60-94], SD = 6.5 years) participated in the study. As a group the female cohort with no known previous diagnosis of osteoporosis were at high risk for fracture over the next five years as evidenced by an average FRACTURE Index score of 6.6 and 7.2 (control and intervention group, respectively) without BMD, and 9.9 and 10.3 (control and intervention group, respectively) with BMD, respectively. At study end, a significant number of participants in the intervention group had initiated the use of calcium or vitamin D supplements (P = 0.016 and P = 0.031, respectively). The initiation of bisphosphonates in eight subjects over the six-month study period was also significant (P = 0.008) in the intervention group. No significant changes in the use of calcium or vitamin D or specific osteoporosis therapies were realized in the control group. In the intervention group, physician contact did not result in a significant increase in the numbers of participants receiving a BMD evaluation. CONCLUSION: As a whole, residents residing in assisted living facilities are at high risk of having osteoporosis and/or sustaining a fracture. When assessment of osteoporosis and fracture risk is communicated to a physician, use of therapies aimed to improve bone health increases. In this study, there was a significant increase in the use of calcium, vitamin D, and bisphosphonates in the intervention cohort. However, physician contact did not result in more participants receiving a BMD evaluation.