A Multi-Objective Approach for Drug Repurposing in Preeclampsia

Preeclampsia is a hypertensive disorder that occurs during pregnancy. It is a complex disease with unknown pathogenesis and the leading cause of fetal and maternal mortality during pregnancy. Using all drugs currently under clinical trial for preeclampsia, we extracted all their possible targets from the DrugBank and ChEMBL databases and labeled them as “targets”. The proteins labeled as “off-targets” were extracted in the same way but while taking all antihypertensive drugs which are inhibitors of ACE and/or angiotensin receptor antagonist as query molecules. Classification models were obtained for each of the 55 total proteins (45 targets and 10 off-targets) using the TPOT pipeline optimization tool. The average accuracy of the models in predicting the external dataset for targets and off-targets was 0.830 and 0.850, respectively. The combinations of models maximizing their virtual screening performance were explored by combining the desirability function and genetic algorithms. The virtual screening performance metrics for the best model were: the Boltzmann-Enhanced Discrimination of ROC (BEDROC)_α=160.9 = 0.258, the Enrichment Factor (EF)_1% = 31.55 and the Area Under the Accumulation Curve (AUAC) = 0.831. The most relevant targets for preeclampsia were: AR, VDR, SLC6A2, NOS3 and CHRM4, while ABCG2, ERBB2, CES1 and REN led to the most relevant off-targets. A virtual screening of the DrugBank database identified estradiol, estriol, vitamins E and D, lynestrenol, mifrepristone, simvastatin, ambroxol, and some antibiotics and antiparasitics as drugs with potential application in the treatment of preeclampsia.     

稀世之宝—铂*

铂是一种化学性质极其稳定的贵金属,铂、铂合金以及铂配合物在催化剂、医药、传感器等领域具有重要应用。简要介绍铂的发现史、自然分布与资源现状、铂的应用等3个方面,其中铂的应用,重点从铂基催化剂、铂合金纳米材料、发光铂配合物、铂类抗癌药物等4个方面展开介绍。     

毒品与化学*

毒品与化学的种种纠葛在2018年中国毒品形势报告中得到了淋漓尽致的体现,因此为做好禁毒工作,必须厘清化学与毒品的关系。从为什么毒品是化学品(毒品的本质),毒品检验和识别,毒品成瘾的本质,由传统毒品到新型毒品的转变等4个方面系统阐述毒品与化学的关系。     

色谱在药物-机体复杂巨系统研究中的应用进展

色谱是一门以分离分析为主,旨在追求复杂事物纯而净的分析化学的重要分支学科。其经过百余年的发展,理论与技术日臻完善,集科学、技术与艺术于一体。近年来,色谱及其与质谱、核磁共振波谱、原子发射光谱等联用技术极大推动了环境、食品、石油化工、生物医药等领域中所涉及复杂体系的研究进展。作为我国传统文化的核心代表,中医药为中国乃至世界人民的健康服务逾千年,从古至今历经上千年临床考验,疗效经久不衰。近年来,中国政府强调继承与创新,加大推进中医药的现代化与国际化。然而中药自身的多成分协同起效复杂性及其与机体时刻新陈代谢变化的复杂性往往相互作用,由此形成了药物-机体复杂巨系统。该复杂巨系统的分析研究是中医药现代化进程的关键瓶颈。色谱的优势在于复杂成分的分离与分析,此恰能为上述复杂巨系统提供技术支撑,色谱及其联用技术已成为推动中医药分子化、数字化、信息化乃至现代化的主流技术。该文综述了色谱及其联用技术在中药复杂体系、复杂生命过程及药物-机体复杂巨系统中的应用进展,介绍了笔者研究团队对中医药现代化的认识、研究思路和研究工作,最后笔者结合对于百年色谱与千年中医药文化之现代化交织的感悟,对色谱技术在此领域的前景做出了展望。     

The Potent Oxidant Anticancer Activity of Organoiridium Catalysts

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η⁵‐Cp^xbiph)Ir(phpy)(Cl)] ( 1‐Cl ), which contains π‐bonded biphenyltetramethylcyclopentadienyl (Cp^xbiph) and C^N‐chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η⁵‐Cp^xbiph)Ir(phpy)(py)]⁺ ( 1‐py ) aquates slowly, and is more potent (in nanomolar amounts) than both 1‐Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1‐py from rapid reaction with intracellular glutathione. The high potency of 1‐py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H₂O₂ by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.     

Aromatic Nitrogen Mustard‐Based Prodrugs: Activity,Selectivity, and the Mechanism of DNA Cross‐Linking

Three novel H₂O₂‐activated aromatic nitrogen mustard prodrugs ( 6 – 8 ) are reported. These compounds contain a DNA alkylating agent connected to a H₂O₂‐responsive trigger by different electron‐withdrawing linkers so that they are inactive towards DNA but can be triggered by H₂O₂ to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross‐link (ICL) formation in the presence or absence of H₂O₂. An electron‐withdrawing linker unit, such as a quaternary ammonia salt ( 6 ), a carboxyamide ( 7 ), and a carbonate group ( 8 ), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5 % cross‐linking formation. However, H₂O₂ can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross‐linking efficiency (>20 %). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard ( 15 ) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI₅₀ of less than 1 μM , whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications.     

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent ( P1–B1 ) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine ( P1–A1 ). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benz[c]acridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1 .     

Design of Enzymatically Cleavable Prodrugs of a Potent Platinum‐Containing Anticancer Agent

Using a versatile synthetic approach, a new class of potential ester prodrugs of highly potent, but systemically too toxic, platinum–acridine anticancer agents was generated. The new hybrids contain a hydroxyl group, which has been masked with a cleavable lipophilic acyl moiety. Both butanoic (butyric) and bulkier 2‐propanepentanoic (valproic) esters were introduced. The goals of this design were to improve the drug‐like properties (e.g., logD) and to reduce the systemic toxicity of the pharmacophore. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum‐assisted, self‐immolative ester cleavage in a low‐chloride environment (LC‐ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase‐2 (hCES‐2) (LC‐ESMS). The valproic acid ester derivatives are the first example of a metal‐containing agent cleavable by the prodrug‐converting enzyme. They show excellent chemical stability and reduced systemic toxicity. Preliminary results from screening in lung adenocarcinoma cell lines (A549, NCI‐H1435) suggest that the mechanism of the valproic esters may involve intracellular deesterification.     

Organocatalytic and Scalable Synthesis of the Anti‐Influenza Drugs Zanamivir,Laninamivir, and CS‐8958

Zanamivir, laninamivir, and CS‐8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D ‐araboascorbic acid by this synthetic route, which relies heavily on a thiourea‐catalyzed enantioselective Michael addition of acetone to tert‐butyl (2‐nitrovinyl)carbamate and an anti‐selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D ‐araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.     

Novel liver-specific nitric oxide（NO） releasing drugs with bile acid as both NO carrier and targeting ligand

Novel liver-specific nitric oxide（NO） releasing drugs with bile acid as both the NO carrier and targeting ligand were designed and synthesized by direct nitration of the hydroxyl group in bile acids or the 3-Ohydroxyl alkyl derivatives,with the intact 24-COOH being preserved for hepatocyte specific recognition.Preliminary biological evaluation revealed that oral administrated targeted conjugates could protect mice against acute liver damage induced by acetaminophen or carbon tetrachloride.The nitrate level in the liver significantly increased after oral administration of 1e while nitrate level in the blood did not significantly change.Co-administration of ursodeoxycholic acid（UDCA） significantly antagonized the increase of nitrate in the liver resulted by administration of 1e.