Small molecules targeting protein-protein interactions for cancer therapy

Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.

Role of scutellarin in human cancer—A review

Scutellarin is a flavone glycoside isolated from Erigeron breviscapus, a perennial herb of the daisy family Asteraceae.The scutellarin-rich extract of E. breviscapus, known as breviscapine, has been used as a traditional Chinese medicineto improve blood circulation and cerebral blood supply. There is increasing scientific evidence affirming that scutellarinpossesses pharmacological properties, notably, anti-cancer properties. This review is focused on scutellarin, itschemistry, and anti-cancer properties. Scutellarin induces apoptosis and cell cycle arrest and inhibits proliferation andprogression of a wide spectrum of human cancer cells. Of particular interest are the multiple molecular targets andpathways of scutellarin, structure-activity relationships of its cytotoxicity, and future research. Sources of informationwere from ScienceDirect, Google Scholar, and PubMed.

Application of benzoxaboroles compounds in medicinal chemistry / 药学学报

Benzoxaborole is a series of compounds with five member ring and boron atom. Since the approval of crisaborole and tavaborole by FDA, benzoxaborole gained lots of research interests and become widely used in current drug discovery. Specially, benzoxaborole derivatives were found to exhibit anti-bacterial, anti-fungal, anti-protozoal, anti-tumor and anti-inflammatory activities. Here, we will review the properties of benzoxaborole, structure activity relationships as well as the recent progress in the biological activity of benzoxaborole derivatives.

Synthesis and cytotoxic activities of E-resveratrol derivatives / 中国天然药物

The present study was designed to synthesize derivatives of E-resveratrol and evaluate their cytotoxic activity in vitro. Different functional groups were conjugated with the phenolic hydroxyl group of E-resveratrol, and the double bond of E-resveratrol was reduced. The in vitro cytotoxicity of the synthetic derivatives was evaluated against three tumor cell lines (A549, LAC, and HeLa) using the MTT assay. Twenty-six E-resveratrol derivatives were synthesized and their structures were confirmed by (1)H NMR, MS, IR, and elemental analyses. Compounds 1-6, 12, 15-21, and 23-26 were reported for the first time. Among them, Compounds 1, 2, 4, 5, and 9-11, showed significant cytotoxicity against tumor cells; especially, Compound 1 showed an IC50 value of 4.38 μmol · L(-1) in the A549 cells which was 15-fold more active than E-resveratrol; Compound 9 showed an IC50 value of 1.41 μmol · L(-1) in the HeLa cell line which was 90-fold more active than E-resveratrol, and close to adriamycin. The structure-activity relationships were also investigated. Compounds 1, 2 and 9-11 may serve as potential lead compounds for the discovery of new anticancer drugs.

Assessment of quantitative structure-activity relationship of toxicity prediction models for Korean chemical substance control legislation

OBJECTIVES: For successful adoption of legislation controlling registration and assessment of chemical substances, it is important to obtain sufficient toxicological experimental evidence and other related information. It is also essential to obtain a sufficient number of predicted risk and toxicity results. Particularly, methods used in predicting toxicities of chemical substances during acquisition of required data, ultimately become an economic method for future dealings with new substances. Although the need for such methods is gradually increasing, the-required information about reliability and applicability range has not been systematically provided. METHODS: There are various representative environmental and human toxicity models based on quantitative structure-activity relationships (QSAR). Here, we secured the 10 representative QSAR-based prediction models and its information that can make predictions about substances that are expected to be regulated. We used models that predict and confirm usability of the information expected to be collected and submitted according to the legislation. After collecting and evaluating each predictive model and relevant data, we prepared methods quantifying the scientific validity and reliability, which are essential conditions for using predictive models. RESULTS: We calculated predicted values for the models. Furthermore, we deduced and compared adequacies of the models using the Alternative non-testing method assessed for Registration, Evaluation, Authorization, and Restriction of Chemicals Substances scoring system, and deduced the applicability domains for each model. Additionally, we calculated and compared inclusion rates of substances expected to be regulated, to confirm the applicability. CONCLUSIONS: We evaluated and compared the data, adequacy, and applicability of our selected QSAR-based toxicity prediction models, and included them in a database. Based on this data, we aimed to construct a system that can be used with predicted toxicity results. Furthermore, by presenting the suitability of individual predicted results, we aimed to provide a foundation that could be used in actual assessments and regulations.

An Analysis of the Electronic Structure of an Imidazo [1,2-a] Pyrrolo [2,3-c] Pyridine Series and Their Anti-Bovine Viral Diarrhea Virus Activity.

The aim of this study was to analyze the relationship between electronic structure and anti Bovine Viral Diarrhea Virus activity in a series of imidazo[1,2-a] pyrrolo [2,3-c]pyridine derivatives. The electronic structure and the local atomic reactivity indices were obtained with density functional theory at the B3LYP/6-31G (d,p) level. A statistically significant equation (n=15, R=0.90, R2=0.82, adj R2=0.77, F(3,11)=16.60 (p<0.0002), outliers>2σ=0, SD=0.29) relating the variation of the antiviral activity with the variation of the electrondonor and electron-acceptor properties of three atoms was obtained. The variation of antiviral potency is orbital-controlled. A partial antiviral pharmacophore is proposed.

Synthesis and cytotoxic activity of 3, 4, 11-trihydroxyl modified derivatives of bergenin / 中国天然药物

To synthesize a series of 3-, 4-, and/or 11-trihydroxy modified bergenin derivatives and evaluated their cytotoxic activity in vitro. The phenolic hydroxyl groups of bergenin were protected by benzyl groups with benzyl bromide. Treatment of dibenzyl bergenin with the corresponding acid in the presence of EDC·HCl and DMAP in CH2Cl2, followed by hydrogenation over Pd/C catalysts, afforded derivatives of bergenin esters. All of the target compounds were identified by IR, MS, and (1)H NMR. Twenty-six novel and three known derivatives of bergenin esters were synthesized. Their cytotoxicity values were evaluated by the MTT assay on the inhibition of DU-145 and BGC-823 cells in vitro. Several triply-substituted (3a, 4a, 5a, 6a, 7a) and doubly-substituted (8b, 9b) bergenin derivatives exhibited higher cytotoxic activity than bergenin. The result showed that the size of substituents and the lipophilicity of the bergenin esters displayed an important role on their cytotoxic activity.

Effects of annonaceous acetogenins against multidrug resistant human breast cancer cell line MCF-7/ADR in vitro / 中草药

Objective: To investigate the effects of 15 annonaceous acetogenins (ACGs) on human breast cancer cell line MCF-7/ADR, and to find out their structure-activity relationship. Methods: MCF-7/ADR cells were treated with 15 ACGs such as annotemoyin-1 (1), annosquamin B (2), annosquamin A (3), annosquamin C (4), annosquacin C (5), urarigrandin A (6), isodesacetyluvaricin (7), annosquacin D (8), annosquacin B (9), 12, 15-cis-squamostatin-A (10), squamostatin-A (11), squamostanin-B (12), squamostanin-A (13), squamostatin-D (14), and squamostatin-E (15) for 48 h, and the inhibition on MCF-7/ADR cells was detected using MTT assay. Results: All the tested compounds showed significant inhibitory activities against MCF-7/ADR cells, and were more potent than the standard control verapamil. The activity of compound 1 was 190 times higher than that of verapamil. Conclusion: The ACGs with more carbons between tetrahydrofuran (THF) ring and γ-unsaturated lactone are more potent. If all other structural features are identical, the ACGs with more hydroxyls on aliphatic chain would be more active, and four hydroxyls might be optimal among bis-nonadjacent-THF ACGs. Moreover, ACGs with stereochemical arrangement of erythro are more active than those of threo, and the compounds with THF ring configuration of cis seem to be superior to those of trans. Furthermore, bis-adjacent-THF ACGs with molecular weight of 622 and with three hydroxyl groups and stereochemical arrangement of erythro partly produce notable cytotoxicity.

Synthesis of caffeic acid ester derivatives and their bioactivities / 中草药

Objective: To design and synthetise the natural products caffeic acid ester derivatives, and to study the lipid metabolic disturbance regulation activity of the derivatives. Methods: Applying caffeic acid as material, the target compounds were prepared by two routes and evaluated for antihyperlipidemic effects in HepG2 cells. Results: Ten caffeic acid ester derivatives were synthesized, and compound C5 has not yet been reported. The structures of the target compounds were identified by spectrum. Pharmacological results showed that eight derivatives had potency of lipid-regulating in different levels. In particular, compounds C3 and C5 showed significant lipid-regulating effects compared to the lead compound caffeic acid and positive drug Simvastatin. Conclusion: Compound C5 is a new caffeic acid ester derivative. The primary structure-activity relationships are discussed in this article.

Progress on the second generation inhibitors of hepatitis C virus NS3/4A serine protease / 国际药学研究杂志

The progress of the second generation inhibitors of HCV NS3/4A serine protease, based on the modifications to the first generation ones (telaprevir, boceprevir, BILN-2061), is reviewed. The second generation inhibitors can significantly improve potency, pharmacokinetic profiles, and to some degree reduce the resistance induced by the first generation ones. The structure-activity relationships of these inhibitors are also discussed.

Anticonvulsant activity of thymoquinone and its structural analogues

It has been widely reported that the crude oil of Nigella sativa L., Ranunculaceae, seeds and its major chemical component thymoquinone present anticonvulsant activity. These facts led us to verify the pharmacological potential of five structurally related para-benzoquinones on the pentylenotetrazol-induced seizures model, and establish the structural characteristics that influence the anticonvulsant activity of thymoquinone. The unsubstituted para-benzoquinone was the compound that exhibited the highest potency, while 2-methyl-p-benzoquinone was inactive. It was found that the presence of alkyl groups attached to the ring influence the pharmacological activity of the para-benzoquinones. In addition, the number, position, and size of these groups change the anticonvulsant potency of the compounds.

Studies on antiestrogen compounds and their structure-activity relationships / 国际药学研究杂志

Antiestrogens have been proven to be highly effective in the treatment of estrogen receptor-dependent breast cancer. According to the mechanism, antiestrogen compounds were mainly categorized as selective estrogen receptor modulators (SERM) and pure antiestrogens, which structurally include estradiol derivatives, triphenylethylenes, benzo heterocyclic and polyphenol of natural compounds. The research advances on the antiestrogen compounds and their structure-activity relationships are reviewed.

Silybin-derived flavonolignans and their structure-activity relationships: Research advances / 国际药学研究杂志

Silybum marianum (L.) Gaertn. is recorded by the pharmacopoeias of many countries to have such bioactivities as antioxidant, anti-hepatocirrhosis, anti-inflammation, immunomodulation and liver regeneration. It has been used clinically to treat hepatitis, fatty liver, liver cirrhosis, ischemic damage, radiation injury, etc. With silybin entering the phase II clinical trial as an anti-cancer drug, its correlative investigations including derivatives preparation, structure-activity relationship (SAR) detection, and the detailed action mechanisms have been developing rapidly. Recently, the new synthetic strategy of silybin and dehydrosilybin (DHS) along with their anti-HSV (herpes simple virus) activity has also been reported. This paper reviews about one hundred preparative derivatives of silybin and DHS which appeared in recent years, with the emphasis on their pharmacological activity and the results of their SAR. The future development direction of structural modification of silybin and DHS is also discussed and predicted.

Flavona e análogos como radioligantes para imageamento cerebral. Síntese, marcação com radioiodo e estudos in vivo frente a sítios receptores benzodiazepínicos / Flavone and analogues as radioligands for brain images. Synthesis, radiolabelled and in vivo studies in benzodiazepine receptor sites

O desenvolvimento de radioligantes para o sistema nervoso central (SNC) com características radiotraçadoras que justifiquem seu uso em diagnóstico por geração de imagens é esperado pela comunidade médica nuclear. Os benzodiazepínicos flumazenil-‘ANTPOT. 11’C e iomazenil-‘ANTPOT. 123’I são utilizados, com limitações, para investigações clínicas de densidade de sítios receptores benzodiazepínicos no cérebro em patologias como Alzheimer, epilepsia e depressão, entre outras. No Brasil, entretanto, estes traçadores ainda não estão disponíveis para uso clínico. Neste sentido, os flavonóides têm despertado interesses como perspectiva de nova classe de compostos com atividade no SNC podendo originar radiotraçadores com perspectivas para aplicação em imageamento cerebral. Baseado no exposto, a proposta deste estudo envolve o planejamento, a síntese e a marcação com radioiodo (‘ANTPOT. 131’I e ‘ANTPOT. 123’I) de flavona e análogos, o controle de qualidade radioquímico, os estudos de biodistribuição e o imageamento, para a avaliação do perfil de captação desses compostos e potencial aplicação em estudos cerebrais, frente a sítios receptores benzodiazepínicos. Os compostos estudados neste trabalho foram obtidos empregando-se a transformação de Baker-Venkataraman. A flavona e análogos foram identificados através de espectros de RMN-1H, RMN-13Ce IV. O grau de pureza das substâncias obtidas foi confirmado através da medição da faixa de fusão. Os compostos radiomarcados foram obtidos com alta pureza radioquímica por substituição eletrofílica aromática direta. Esta marcação propiciou estabilidade in vitro após 24 horas e, para a flavona radiomarcada estabilidade in vivo, uma vez que a tireóide não apresentou captação significativa em tempos menores que 1 hora e excreção favorável no tempo de 24 horas

The development of radioligands for the Central Nervous System (CNS) with adequate radiotracer characteristics for the use in imaging diagnostic has been long expected by the medical community. Benzodiazepines flumazenil-11C and iomazenil-123I are employed with limitations in clinical investigations of the density of receptor sites in the brain in pathologies such as Alzheimer, epilepsy, and depression. Nevertheless, in Brazil these radiotracers are not available in market, yet. In this respect, flavonoids has drawing attention as a perspective of a new class of compounds wit CNS activity and potential of originating radiotracers to be employed in brain imaging. Therefore, the goal of this work consisted in the planning, synthesis, and labeling with radioiodine (131I and 123I) of flavone and analogs, as well as to perform radiochemical quality control, biodistribuction, and imaging studies of the radiotracers obtained in order to evaluate the uptake profile and potential for use in cerebral studies of benzodiazepinic receptors sites. To obtain the compounds, we utilized the Baker-Venkataraman transformation, and NMR-1H, NMR-13C, and IR spectroscopy were employed for identification of the molecules. The purity of the compounds obtained was assessed by means of melting point determinations. The radiolabeled compounds were obtained by aromatic electrophilic substitution with a high degree of radiochemical purity. The labeling allowed in vitro stability after 24 hours and in vivo stability of the radiolabeled flavone, provided that the thyroid did not presented significant uptake in less than one hour and favorable excretion in 24 hours. Biodistribution studies were carried out employing Swiss mice. The results indicated high concentrations of flavone-I131 in the brain, especially in the first 30 minutes after intravenous injection, as well as favorable elimination after 24 hours. Brain images were obtained from New Zeland rabbit and Wistar rats in analogical gamma camera, suggesting that short-time brain uptake of the radioligand (up to 30 minutes) allows the acquisition of cynthilographic images. Additionally, molecular modeling studies of the flavone were performed employing the semi-empiric method of AM1. The results corroborate the chemical reactivity of the compound for labeling with radioiodine by aromatic electrophilic substitution, process that is governed mainly by electrostatic interactions. The individual values of Mulliken, Natural, and Electrostatic charges of each carbon atom in flavone structure were calculated and topographic maps of charge distribution were then generated. The analysis of the maps indicates that positions 6 and 8 in the flavone molecule are most likely to present the radioiodine substitution

The homotrimeric structure of HtrA2 is indispensable for executing its serine protease activity

Serine protease activity of high temperature requrement 2 (HtrA2) is essential for promoting cell death, as well as for protecting against cellular stresses. An X-ray crystallographic study described the formation of a pyramid shaped homotrimer that is a proteolytically competent form of HtrA2; however, little is known about effects of the trimeric structure of HtrA2 on the natural substrates. In this study, we generated the HtrA2 protein that has a single point mutation at the homotrimerization motif to assess relationship between structure and the proteolytic activity of HtrA2 on its substrates. Using gel filtration, a native gel electrophoresis system, and a co-precipitation assay, we confirm that phenylalanine 149 in HtrA2 is a crucial determinant for the formation of the HtrA2 homotrimeric structure. Moreover, we described that the HtrA2 monomeric form abolished not only autoproteolytic activity, but also the proteolytic activity against XIAP (X-linked inhibitor of apoptosis protein) known as the HtrA2 substrate. Taken together, the results indicate that the homotrimeric structure of HtrA2 is required for executing its serine protease activity.

PROGRESS IN THE INVESTIGATION ON CONOTOXINS / 中国海洋药物

This review largely deals with the peptide toxins elaborated by marine cone snails of the genus Conus . Each species of Conus contains in its venom 50 to 200 different peptides directed at different macromolecular targts. These include competitive antagonists of postsynaptic nicotinic receptors (a-conotoxins), blockers selective for Na+ channels in skeletal muscle (u- conotoxins), blockers of presynaptic of antagonists of postsynaptic Ca2+ channels (w-conotoxins), activators of Na+ channels (s-conotoxins), blockers of K+ channels (k-conotoxins), blockers of nicotinic receptor channels (u-conotoxins) and antagonists of NMDA receptors (cono-sleeper).The small size of the peptides (13 to 30 residues is typical) has facilitated synthesis of many of them. A very attractive feature is the highly cross-linked conserved 2 to 3 disulfide bonds which make conotoxins conformationally rigid, some of conotoxins, however, are stabilized by r-carboxyglutamates. The Structure-Activity Relationships of conotoxins and a brief perspective have been reviewed in the paper.