Design, synthesis and biological evaluation of HIV-1 protease inhibitors with morpholine derivatives as P2 ligands in combination with cyclopropyl as P1' ligand.
以吗啉衍生物为 P2 配体与环丙基为 P1 '配体的 HIV-1 蛋白酶抑制剂的设计、合成及生物学评价.
- 作者列表："Dou Y","Zhu M","Dong B","Wang JX","Zhang GN","Zhang F","Wang YC
:A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1' ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.
设计并合成了一系列新型 HIV-1 蛋白酶抑制剂，包括以吗啉衍生物为 P2 配体，以疏水性环丙基为 P1 '配体, 旨在改善 HIV-1 蛋白酶活性位点与抑制剂之间的相互作用。合成并评价了 28 个化合物，其中抑制剂 m18 和 m1 对 HIV-1 蛋白酶的活性表现出良好的抑制作用，IC50 值分别为 47 nM 和 53 nM。M1 的分子建模揭示了抑制剂和蛋白酶之间可能的氢键或范德华，值得深入研究。
METHODS:BACKGROUND:Ultrasound has been demonstrated to accurately diagnose rectal deep endometriosis (DE) and pouch of Douglas (POD) obliteration. The role of ultrasound in the assessment of patients who have undergone surgery for rectal DE and POD obliteration has not been evaluated. AIM:To describe the transvaginal ultrasound (TVS) findings of patients who have undergone rectal surgery for DE. MATERIALS AND METHODS:An observational cross-sectional study at a tertiary care centre in Sydney, Australia between January and April 2017. Patients previously treated for rectal DE (low anterior resection vs rectal shaving/disc excision) were recruited and asked to complete a questionnaire on their current symptoms. On TVS, POD state and rectal DE were assessed. Correlating recurrence of POD obliteration and/or rectal DE to surgery type and symptoms was done. RESULTS:Fifty-six patients were contacted; 22/56 (39.3%) attended for the study visit. Average interval of surgery to study visit was 52.8 ± 24.6 months. Surgery type breakdown was as follows: low anterior resection (56%) and rectal shaving/disc excision (44%). The prevalence of POD obliteration was 16/22 (72.7%) intraoperatively and 8/22 (36.4%) at study visit, as per the sliding sign. Nine patients (39.1%) had evidence on TVS of recurrent rectal DE. Recurrence of POD obliteration and rectal DE was not associated with surgery type or symptomatology. CONCLUSION:Despite surgery for rectal DE, many patients have a negative sliding sign on TVS, representing POD obliteration, and rectal DE. Our numbers are too small to correlate with the surgery type or their current symptoms.
METHODS::Minimally invasive surgery for complex endometriosis requires preoperative planning that intimately connects the gynecologic surgeon to the radiologist. Understanding the surgeon's perspective to endometriosis treatment facilitates a productive relationship that ultimately benefits the patient. We examine minimally invasive surgery for endometriosis and the key radiologic information which enable the surgeon to successfully negotiate patient counseling, preoperative planning, and an interdisciplinary approach to surgery.
METHODS:STUDY OBJECTIVE:Prior research collectively shows that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN:Cross sectional study among women with no prior diagnosis of endometriosis. SETTING:Fourteen clinical centers in Salt Lake City, Utah and San Francisco, California. PATIENTS:Four hundred and ninety five women, ages 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS:Gynecologic laparoscopy/laparotomy, regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS:Participants underwent anthropometric assessments, body composition, and body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised ASRM staging (I to IV) and typology of disease (superficial [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. While the majority of confidence intervals were wide and overlapping, three general impressions emerged: 1) women with versus without incident endometriosis had the lowest anthropometric/body composition indicators; 2) women with stage I or IV had lower indicators compared to women with stage II or III; and 3) women with OE and/or DIE tended to have the lowest indicators, while women with SE had the highest indicators. CONCLUSION:Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.