雷西莫特:一种潜在的多适应证免疫调节药物

雷西莫特是咪喹莫特的类似物,在体外和体内都具有免疫调节作用.作为Toll样受体7和Toll样受体8激动剂,雷西莫特能刺激免疫细胞产生大量的炎性细胞因子,在促进T h1反应的同时抑制T h2反应,发挥抗病毒、抗肿瘤及抗过敏性疾病等作用.本文对雷西莫特的药物化学性质、药理作用、临床应用等进行全面综述,以期为其在皮肤科及相关...     

1-氨基茚的合成

目的：合成1-氨基茚。方法：以苯丙酰氯为初始原料，经3步反应合成1-氨基茚。由TLC确定每步反应终点。结果：目标化合物结构经MS确证，纯度经GSMS测定达97．8％。结论：该法合成了1-氨基茚，收率达39．2％。     

咪喹莫特的合成

目的：研究抗病毒药咪喹莫特的合成。方法：以邻氨基苯甲酸为起始原料经缩合、环合、氯化、还原、N-氧化,氨基化等反应合成咪喹莫特。结果：合成的咪喹莫特收率为39％（以3-硝基4-羟基喹啉计）。经元素分析、MS、UV、IR、HNMR等测试确证了结构。结论：本方法合成咪喹莫特原料价廉易得,适合工业化生产。     

盐酸莫雷西嗪的合成

目的：合成抗心律失常药盐酸莫雷西嗪。方法：以3-溴硝基苯、乙酰苯胺为原料经烃化、水解反应得3-硝基二苯胺，经硫化亚铁-氯化铵-甲醇-水体系还原得3-氨基二苯胺，再经酰化、环合、烃化和成盐反应得盐酸莫雷西嗪。结果：合成了盐酸莫雷西嗪，9步反应总收率为35．8％。目标产物的结构经核磁共振氢谱、质谱确证。结论：本合成方法原料易得，操作简单，收率较高，适合大规模制备。     

头孢他啶侧链酸及其活性硫酯的合成研究

研究以乙酰乙酸乙酯等原料合成头孢他啶侧链酸及其活性硫酯的方法，即以乙酰乙酸乙酯为起始原料，经肟化、溴化、成环3步反应合成去甲氨噻肟乙酸乙酯[2-氨基-α-羟亚氨基-4-噻唑乙酸乙酯]；再经醚化、水解、酰化反应合成其活性硫酯-{（Z）-2-氨基-α-[[『2-（叔丁氧基）-1,1-二甲基-2-氧代乙氧基]亚氨基]-4-噻唑乙酸}2＇-苯并噻唑基硫酯。     

西米考昔的合成*

目的：合成西米考昔。方法：以4-（乙酰氨基）苯磺酰氯为原料，通过6步反应合成目标化合物。结果和结论：目标化合物经元素分析、核磁共振氢谱、红外光谱和质谱确证其化学结构，总收率达51．6％。     

5-氨基水杨酸类衍生物的合成

目的 寻找活性强，副作用小的5-氨基水杨酸衍生物，本文设计并合成新的5-氨基水杨酸衍生物。方法 以水杨酸为起始原料，通过硝化、酰化、卤化反应，制得酰氯，与对乙酰氨基酚相偶联，合成了新的5-氨基水杨酸衍生物。结果 化合物的结构经红外光谱、核磁共振氢谱、碳谱及元素分析确证。结论 该合成方法成功地合成了新的5-氨基水杨酸类衍生物。     

N-[5-氨基水杨酰基]甘氨酸的合成

[目的]改进N-[5-氨基水杨酰基]甘氨酸的合成方法，使之更适合工业化生产，[方法]以5-硝基水杨酸为起始原料合成N-[5-氨基水杨酰基]甘氨酸，经缩合，还原和水解等三步反应合成了N-[5-氨基水杨酰基]甘氨酸。[结果]较文献报道工艺简单，反应条件温和。产物结构经红外光谱，核磁共振氢谱及质谱确证。[结论]此合成路线是完全可行的。     

7-氨基-3-(丙-1-烯基)-4-头孢烷酸的合成

目的：研究头孢丙烯中间体7-氨基-3-(丙-1-烯基)-4-头孢烷酸的合成工艺。方法：以GCLE为起始原料,经Wittig反应、脱4、7位保护基制得产品。控制反应原料的纯度、反应温度。结果：总收率达到60％。结论：该合成工艺原料易得,反应条件较温和,有一定的工业生产价值。     

1-氨基-γ-咔啉衍生物合成方法的研究

目的 研究1-氨基-γ-咔啉衍生物的合成方法，制备了1-(3′-二甲氨基丙胺基-γ-咔啉。方法 以吡啶为原料经N-氧化、硝化、重排等反应制得关键中间体4-羟基吡啶-2-酮，再经Fische，重排环合、卤代、Cu^ 催化、N-烃化，共8步反应合成目标化合物。结果与结论 以吡啶计算，总收率约5％。目标化合物的结构经核磁、质谱、高分辨质谱等光谱确证。     

pH-Responsive Nanoparticles for Multidimensional Combined Chemo-Immunotherapy of Cancer

Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple components of this multi-cellular ecosystem need to be targeted simultaneously for successful cancer therapy. The objective of this study was to develop a multidimensional combined chemo-immunotherapeutic modality for effective breast cancer treatment. TLR 7/8 agonist resiquimod was identified as a potent macrophage stimulant in an initial screening. To deliver paclitaxel as a chemotherapeutic drug and resiquimod as an immune activator in a tumor-targeted fashion, two different pH-sensitive nanoparticles were synthesized using two different polymers, a linear PLGA and a multi-arm, star-shaped PLGA. The star-PLGA pH-responsive nanoparticles exhibited improved pH-dependent drug release and increased penetration in a complex breast cancer spheroid model (breast cancer cell + macrophage cell). Treatment with paclitaxel and resiquimod encapsulated in the pH-responsive nanoparticles resulted in increased cancer cell death and macrophage activation, as tested in an in-vitro breast cancer spheroid model. Altogether, the current study suggests that the paclitaxel and resiquimod combination has potent chemo-immunotherapeutic activity, and delivery using a pH-sensitive nanoparticle further improves its efficacy.     

Resiquimod 3M

3M Pharmaceuticals is developing a topical formulation of resiquimod as an immunomodulator for the potential treatment of herpes simplex virus (HSV) infections. As of September 2001, resiquimod was to be commercialized worldwide in association with Eli Lilly. Phase III trials for the treatment of HSV infection were initiated in November 2000 and were ongoing in September 2001. In October 2001, US and European filings were scheduled for 2004, and by February 2002, Lilly was anticipating launch in either 2004 or 2005. The compound has also been investigated for the potential treatment of various other diseases, including other viral infections and eczema and as a vaccine adjuvant.     

Resiquimod,a topical drug for viral skin lesions and skin cancer

Introduction: Resiquimod is an immune response modifier which stimulates cells through a toll-like receptors (TLR) 7 and 8 dependent pathway resulting in activation of immune responses that are effective against viral and tumor lesions.

Areas covered: Studies on genital herpes, hepatitis C and actinic keratosis (AK) as well as papers of molecular activities of resiquimod were identified by a PubMed search. Although effective against genital HSV-2 in animal models, development of topical resiquimod for the treatment of recurrent genital herpes in humans was stopped due to inconsistent results in clinical trials. Reduction of HCV viral load was achieved by oral application but was associated with unacceptable side effects. Topical treatment of AK was well tolerated and effective with clearance rates higher compared to imiquimod. The molecular mode of action underlying the clinical efficacy primarily depends on cytokine induction in TLR7/8 expressing dendritic cells in the skin.

Expert opinion: Topical resiquimod was shown to be a safe and effective treatment option for AK and appears to have potential as a treatment modality for patients with extended skin areas affected with AK (field cancerization). Resiquimod may also have potential for the therapy or prevention of epithelial viral infections.     

Discovery of Imidazoquinolines with Toll-Like Receptor 7/8 Independent Cytokine Induction

Toll-like receptors (TLRs) are key targets in the design of immunomodulating agents for use as vaccine adjuvants and anticancer treatments. The imidazoquinolines, imiquimod and resiquimod, have been shown to activate TLR-7 and -8 which in turn induce cytokine production as part of the innate immune response. Herein, we report the synthesis and discovery of a C7-methoxycarbonyl derivative of imiquimod that stimulates cytokine production but is devoid of TLR-7/8 activity. Data is presented that shows this analog not only induces IL-12p40 and TNF production, similar to that of imiquimod and resiquimod, but greatly enhances the production of IL-1β, a key cytokine involved in activation of CD4 T cells. It is further demonstrated that TLR-7/8 activation can be recovered by the addition of a C2-alkyl substituent to this newly discovered analog. The results support the existence of an alternative mechanism of action by which imidazoquinolines can stimulate cytokine production.     

Resiquimod,a TLR7/8 agonist,promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells

Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice, subsequently suppressing the host immune system. MDSCs represent a group of immature myeloid cells expressing CD11b and Gr-1. Here, we show that a Toll-like receptor (TLR) agonist, resiquimod, which binds to TLR7 and TLR8, induces the differentiation of MDSCs into mature myeloid cells. MDSCs were isolated from mice bearing mammary carcinoma 4T1 cells, and the purified MDSCs were cultured in the presence of resiquimod for 5 days. Phenotypic analysis showed that the resiquimod-treated MDSCs differentiated into F4/80⁺ macrophages and CD11c⁺/I-A^d+ dendritic cells. Functional analysis showed that the MDSCs also lost their suppressive activity on T cells. Resiquimod-treated MDSCs significantly enhanced the proliferation of T cells that were treated with anti-CD3 and anti-CD28 monoclonal antibodies. These results show that resiquimod induces the differentiation of MDSCs into macrophages and dendritic cells, and also suggest that resiquimod may improve cancer immunotherapy by reducing immunosuppressive MDSCs.     

Investigative drugs for the treatment of cutaneous T-cell lymphomas (CTCL): an update

Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis.

Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody.

Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.     

Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation

Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to dose-limiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DL-lactic acid) (mPEG-PLA) and mixed poly(DL-lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles. We show that these particles are taken up mainly by dendritic cells and macrophages, which are the prime initiators of anticancer immune responses. Nanoparticles loaded with resiquimod activate these cells, demonstrating the availability of the immune-stimulating cargo. The unloaded particles are non-inflammatory and do not have cytotoxic activity on immune cells. Following subcutaneous injection in mice, mPEG-PLA and PLGA/mPEG-PLA nanoparticles are detected in dendritic cells and macrophages in the draining lymph nodes, demonstrating the targeting potential of these particles. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy.     

Resiquimod: a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses

Genital herpes is one of the most common sexually transmitted diseases worldwide. Currently, there are three FDA-approved nucleoside analogs and other therapies such as foscarnet and cidofovir used to treat genital herpes. Resiquimod, the latest immune response modifier (IRM), has shown in vivo evidence of efficacy against herpes simplex virus (HSV) type 2. The first clinical trial involving resiquimod demonstrated that it reduced the recurrence rate of genital herpes, but phase III trials were suspended due to lack of efficacy. Resiquimod shows promise for other viral infections and as a vaccine adjuvant.     

The role of topical immune response modifiers in skin cancer

Topical immune response modifiers include imiquimod and resiquimod. The mechanism of action of immune response modifiers is complex and not completely understood. It involves the stimulation of innate and cell-mediated immune responses through Toll-like receptor-mediated induction of cytokines. Imiquimod is approved for the treatment of actinic keratoses, superficial basal cell carcinomas and warts; it has also been documented to successfully treat other forms of skin cancer such as squamous cell carcinoma in situ, melanoma and extramammary Paget's disease.     

Targeting the Toll-like receptor 7 pathway in asthma: a potential immunomodulatory approach?

In allergic airways, as in asthma, inflammation and impaired functioning of toll-like receptor 7 (TLR7) has been found. The augmentation of this receptor with agonist compounds resulted in bronchodilation and a switch of the T(H)2 inflammatory pattern, specific for allergic conditions, to T(H)1 inflammation, characterised by an increased production of interferon-γ. This was a preclinical study evaluating the effects of two TLR7 agonists, imiquimod and resiquimod, on the isolated guinea pig trachea. The TLR7-related downstream signalling pathways were also assessed. Both TLR7 agonists were shown to reduce serotonin-induced bronchoconstriction, which is possibly exerted via the p38MAPK and NF-κB pathways. Therapeutic targeting of TLR7 with specific agonists might represent a promising immunomodulatory approach in asthma, especially if systemic exposure is minimised with inhaled formulations.