抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of...

Bioavailability of curcumin: problems and promises.

Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

Anal. Calcd for C13H90aNb: C, 58.42; H, 3.39; N, 26.21. Found: C, 58.40; H, 3.39; N, 26.15. Reaction of N~Carbomethoxy-6-carbethoxy-2-azabicyclo[t.l.O]hex-3-ene (2b) with Dimethyl Acetylenedicarboxylate. To a Pyrex tube was added 316 mg of 2b and 228 mg of DMAD. The tube was flushed with argon and sealed. The reaction mixture was heated in an oil bath a t 170' for 24 hr. Nmr analysis, by comparing the bridgehead to total methoxyl hydrogens of the crude product, reveals an 87% yield of 9. The product was purified first by molecular distillation and then by vapor phase chromatography (I f t X 0.25 in., 212O, 3% SE-30 on Chromosorb Cr 60/70, He 50 cc/min): nmr (CDC13) 7 3.38-3.73 (m, 1 H), 4.12-4.47 (m, 1 H), 4.42 (s, broad, W112 = 3 Hz), 5.75 (9, J = 7 Hz, 2 H), 6.18 (s, 6 H), 6.32 (s, 3 H), 6.68-6.83 (m, 1 H), and 8.53 (t, J = 7 Hz, 3 H); ir (neat) 1721 (C=O) and 1645 cm-* (C=C). Anal. Calcd for C16H19N08: C, 54.39; H, 5.42. Found: C, 54.12; H, 5.42. Attempts to purify the above product by preparative thin layer chromatography (20 X 20 X 0.2 cm silica gel, 3:l ether-benzene) resulted in the production of isomeric compound 11: nmr (CDC13) T 3.17-3.38 (m, 1 H), 4.55 (s, broad, W i p ~ = 2.5 Hz, 1 H), 4.90 (d, broad, Wllz = 3 Hz, 1 H), 5.77 (9, J = 7 Hz, 2 H), 6.20 (s, 3 H), 6.22 (s, 3 H), 6.30 (s, 3 H), 6.87-7.95 (m, 2 H), and 8.80 (t, J = 7 Hz, 3 H); ir (neat) 1726 cm-l (C=O). Anal. Calcd for C16H19NO8: C, 54.39; H, 5.42. Found: C, 54.11; H, 5.25. Kinetics of t he Cycloaddition of 2 with Dimethyl Acetylenedicarboxylate. To an nmr tube were added controlled amounts of 2a or 2b, DMAD, and CsDe. CsHs was used as an internal standard with the total volume being recorded. (The initial concentration of reactants was approximately 1 M.) The tube was flushed with nitrogen, sealed under vacuum, and maintained a t the appropriate temperature (*O.l') in an oil bath. Determinations for 2a were made a t 70.5, 80.7, and 91.4' while for 2b determinations were made a t 106.3, 113.6, and 120.9'. The disappearance of 2a was monitored by periodic integration of the upfield endo cyclopropyl peak in the nmr spectrum of the reaction mixture. The disappearance of 2b was followed by periodic integration of the cyclopropyl proton a t position 5 in 2b. Second-order rate constants and activation energies were obtained by least-squares fitting.

Reactions of N-aryl nitrogen oxides. 1. Selective ortho chlorination in the reactions of aryl nitrones and amine oxides with thionyl chloride or phosgene

The chemokine CXCR4 receptor is a G-protein-coupled receptor that has multiple functions in normal physiologies involving the hematopoietic and immune systems. Although the CXCR4 receptor was initially discovered as one of the co-receptors involved in human immune deficiency virus (HIV) cell entry, it has also been linked to many central immune system functions through the direct regulation of cell trafficking and adhesion, and is present in many cell types within the body. The receptor ligand combination of CXCL12 (SDF-1) and CXCR4 underlies pathologies such as HIV infection, cancer metastasis and drug resistance, leukemia progression, rheumatoid arthritis, and lupus. This alternative and widespread functionality has allowed researchers to discover new potential uses for substances that are CXCR4 antagonists. This has resulted in approval of the first CXCR4 antagonist, plerixafor injection (AMD3100), for hematopoietic stem cell mobilization. Newer agents are under clinical evaluation for HIV, cancer, and stem cell mobilization. As these agents are further investigated, new uses and therapeutic interventions for CXCR4 antagonists will be discovered. Drug Dev Res 72:598–602, 2011. © 2011 Wiley Periodicals, Inc.

https://scholarblogs.emory.edu/liotta/files/2014/08/226.pdf

Emergence of small‐molecule CXCR4 antagonists as novel immune and hematopoietic system regulatory agents

Rearrangement of α-Phenylselenenylketones

The chemokine receptor CXCR4 plays an integral role in the development of highly metastatic breast cancer and in the pathogenesis of chronic HIV infection. In this study, we compared the effects of CXCR4 antagonists on apoptosis induction in hematopoietic cells and in tumor cells. We incubated cells expressing CXCR4 with a series of CXCR4 antagonists and subsequently exposed the cultures to a pro-apoptotic peptide derived from the HIV-1 Nef protein (NefM1). The NefM1 peptide contains residues 50-60 of Nef and was previously shown to be the sequence necessary for Nef to initiate the apoptotic program through CXCR4 signaling. We found that several of the compounds studied potently blocked Nef-induced apoptosis in Jurkat T-lymphocyte cells. Interestingly, many of the same compounds selectively triggered apoptosis in MDA-MB-231 breast cancer cells, in some cases at sub-nanomolar concentrations. None of the compounds were toxic to lymphocyte, monocyte or macrophage cells, suggesting that aggressive breast cancer carcinomas may be selectively targeted and eliminated using CXCR4-based therapies without additional cytotoxic agents. Our results also demonstrate that not all CXCR4 antagonists are alike and that the observed anti-Nef and pro-apoptotic effects are chemically tunable. Collectively, these findings suggest our CXCR4 antagonists have promising clinical utility for HIV or breast cancer therapies as well as being useful probes to examine the link between CXCR4 and apoptosis.

/pdf/small-molecule-cxcr4-antagonists-block-the-hiv-1-nef-cxcr4-3l2scklls7.pdf

Small molecule CXCR4 antagonists block the HIV-1 Nef/CXCR4 axis and selectively initiate the apoptotic program in breast cancer cells

The invention provides sulfur-linked and nitrogen-linked peptidic conjugates of curcumin analogs that can provide increased water solubility and photostability as compared to the corresponding unmodified curcumin analogs without sacrificing therapeutic efficacy. The conjugates, which are believed to act as prodrugs, can be used therapeutically in the same manner as the unmodified curcumin analogs, such as in the treatment or prevention of cancer, diabetes, or inflammatory diseases. One conjugate comprises 3,5-Bis-(2-fluorobenzylidene)-piperidin-4-one, or a salt thereof, covalently attached through a sulfur linkage to a thiol-containing peptide such as glutathione.

Dennis C. Liotta

Papers

Reactions of N-aryl nitrogen oxides. 1. Selective ortho chlorination in the reactions of aryl nitrones and amine oxides with thionyl chloride or phosgene

Emergence of small‐molecule CXCR4 antagonists as novel immune and hematopoietic system regulatory agents

Rearrangement of α-Phenylselenenylketones

Small molecule CXCR4 antagonists block the HIV-1 Nef/CXCR4 axis and selectively initiate the apoptotic program in breast cancer cells

Prodrugs of curcumin analogs