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  • 119 Reads
Human Hyal‑1 – from in silico–Pharmacophore Modeling to in vitro Inhibitor Screening
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The endoglycosidase hydrolase Hyaluronidase 1 (Hyal‑1) is one of five functional hyaluronidases in human body. Degradation of high molecular weight hyaluronan (HA) is mainly catalyzed by Hyal-1 into smaller fragments. These fragments have inflammatory and angiogenic effects.1 The role of Hyal-1 in cancer progression, e. g prostate or bladder, has been discussed for a long time. In several cancer cells, the expression level of Hyal-1 was elevated in comparison to not malignant cells, resulting in higher Hyal‑1 activity and tumor progression.2,3 Although Hyal‑1 is an interesting target for pharmaceutical purposes, no potent inhibitors have been found so far. The enzyme source seems to be the bottleneck in investigation of potent inhibitors. Production of active Hyal‑1 is one of the most challenging tasks. Eukaryotic extraction and purification is very time consuming and expensive. Recombinant expression in bacteria leads to inactive Hyal-1 forming inclusion bodies. Therefore, potent Hyal-1 inhibitors, like chemical compounds or plant extracts, are routinely screened against bovine testis hyaluronidase, which has an amino acid sequence identity of approx. 40 % compared to human Hyal‑1. This again causes problems in interpretation of the obtained data, development of a pharmacophore model or searching for leader compounds inhibiting human Hyal‑1. Using Autodisplay technology, we are able to express human Hyal-1 on the surface of Escherichia coli in an active form.4 With this system, it is possible to screen compounds, directly using the desired target. A combination of pharmacophore modeling followed by docking studies using a virtual system, helped us to get first impressions about binding of the substances to Hyal-1. Next, screening the best hits with whole-cells displaying Hyal-1 seems to be a promising way to find the needle in the haystack.


  1. Stern, R. Semin Cancer Biol. 2008, 18, 275-280
  2. Lokeshwar, V.B.; Obek C.; Pham H. T.; Wei D; Young M. J.; Duncan R.C.; Soloway M. S.; Block N. L. J Urol, 2000, 163, 348-356.
  3. Lokeshwar, V. B.; Rubinowczi D.; Schroeder G. L.; Forgacs E.; Minna J. D.; Block N. L.; Nadji M.; Lokeshwar B. L. J Biol Chem, 2001, 276, 11922-11932.
  4. Orlando Z.; Lengers I.; Melzig M. F.; Buschauer A.; Hensel A.; Jose J. Molecules, 2015, 20, 15449-15498.
  • Open access
  • 257 Reads
Reactivity under Microwave Irradiation of 2-Amino 4H-chromene-3-carbonitrile as Tool for the Construction of Potential Bioactive Derivatives
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Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

4H-Chromenes (or 4H-benzopyranes) and their derivatives are components of many naturally occurring products, which have also been submitted to structural modifications to increase molecular diversity for potential medicinal properties. In this context and starting from the 2-amino-2H-benzopyran-3-carbonitrile platform, it was possible to built easily (20 min.) a new class of 4-imino-3-phenyl-3,4-dihydro-1H-chromeno[2,3-d]pyrimidine-2(5H)-thiones (55-70%) under microwave irradiation at 120°C in pyridine medium. Treatment of the amino-4H-chromene platform with orthoester gave the corresponding methanimidate intermediate, which is converted into formamidine derivatives (63-85%) from various cyclic secondary amines or into N-3 substituted 4H-benzopyrano[2,3-d]pyrimidine-4(5H)-imines (49-94%) under microwave irradiation (50-120 °C, 30 min.). The biological properties of all products were explored by in vitro cancer assays against a panel of seven tumor cell lines (Huh 7D12, Caco2, MDA-MB231, HCT116, PC3, NCI-H727, HaCat, fibroblasts which are representative of different cancers: leukemia, melanona, and cancers of liver, colon, breast, prostate, lung, and kidney) and also by in vitro Serine/Threonine protein kinase inhibition assays (HsCDK5-p25, GSK3a/b, CLK1, HsHaspin, HsPIM1, HsAurora B). Some of these 2-imino- or 2-amino-2H-benzopyran-3-carbonitriles are active against tumor cell lines (Huh7, Caco 2, HCT 116) or protein kinases (CLK1).

  • Open access
  • 74 Reads
Phenotypic Screening on ‘Pathogen Box’ Yielded Novel Antiparasitic Compounds in Leishmania infantum

Leishmanioses are zoonotic diseases caused by intracellular protozoans of the genus Leishmania. Recent research has revealed the extensive distribution and expansion of canine leishmaniosis in large areas of the world, where the high prevalence of canine infection is associated with an increased risk of human disease. There are not specific pharmacologic treatments for canine leishmaniasis. The only way to manage the situation is the euthanasia of the infected dogs. The sacrifice of the dog was used to try to control the expansion of the infection since decades without success. Also there is a lot of other animal species that can act as host for the disease, also with human contact. Then, to achieve a solution, we must develop a vaccine or a specific drug for canine leishmaniasis. The Pathogen Box is a project led by Medicines for Malaria Venture (MMV, Switzerland; that aims to identify novel drugs with activity against diseases such as tuberculosis, malaria, toxoplasmosis, and dengue, among others. The box consists of 400 mostly novel synthetic chemicals that were initially selected from a set of ~4 million compounds due to their low toxicity for mammalian cells and activity against specific microbial pathogens. In fact, the compounds display cytotoxicity at levels that are thought to be reasonable for drug discovery programs. In this study, we screened the Pathogen Box compounds for antiparasitic activity against Leishmania infantum (reference strain and clinical isolates). This screen led to the discovery of 5 novel hits for drug development and drug design.

  • Open access
  • 125 Reads
Arylideneketones with Potent Trypanosomicidal Activity that Causes Late Apoptosis/Necrosis Like Nifurtimox

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America, despite recent advances in the control of its vector-borne and transfusion mediated transmission. Moreover, migration of infected people has spread the disease to non-endemic areas, presenting a new worldwide challenge. The chemotherapy employed to control the parasitic infection is based on two drugs: Nifurtimox (Nfx) and Benznidazole (Bnz), requiring long-term treatment that can give rise to severe side effects. They are not active against all T. cruzi strains, exhibit low efficiency in long-term chronic infections, and are mutagenic.  The search of new drugs is an urgent need. In this work, we used three symmetrical diarylideneketones containing thiophene and furane ((1E,3E,6E,8E)-1,9-Di(furan-2-yl)nona-1,3,6,8-tetraen-5-one (1), (2E,6E)-2,6-Bis((E)-3-(furan-2-yl)allylidene)cyclohexanone (2) and (2E,5E)-2,5-Bis[3-(thiophen-2-yl)allyliden]cyclopentanone (3)). These molecules showed good to excellent trypanosomicidal activity and selectivity to the parasite, affected cruzipain, a proteolytic enzyme of the parasite, and the glycolytic enzyme, triosephosphate isomerase of T. cruzi (TcTIM) without affecting human´s TIM and showing effectiveness in protecting infected mice and without  toxic effects in vivo. In addition, these could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases. The type of T. cruzi death caused is an important feature to determine, because it could govern inflammation events unbeneficial in the elimination of the parasite. We studied the mechanism of T. cruzi death using Annexin V and propidium iodide followed by flow cytometry analysis of epimastigote treated with the arylideneketones (1, 2, and 3). The arylideneketones along with Nfx and Bnz were evaluated at 24 h post- incubation with the parasite at 5X,  10X and 20X IC50. Arylidenketones 1 and 2 causes after 24 h late apoptosis/necrosis at a concentration of 20 times the value of its IC50 (approximately 80% of late apoptosis/necrosis) as Nfx. This necrotic effect of Nfx was also observed in our previous study by TUNNEL and 1H NMR. It should be studied what happens with compound 3 since no death is observed by apoptosis or necrosis at a dose of 20 times the value of their IC50 as Bnz. Probably, an autophagy process could be ongoing. Currently, we are performing studies in this sense.

Acknowledgments: This work was supported by CSIC, PEDECIBA and Elena Aguilera is recipient of a ANII doctoral fellowship.

  • Open access
  • 102 Reads
Search of Trypanosomicidal Active Principles by Metabolomic-guided Fractionation in Baccharis trimera

The American Trypanosomiasis, also known as Chagas disease is caused by Trypanosoma cruzi, a protozoan of the Trypanosomatidae Family. It is a zoonotic endemic that affects approximately 6-8 million people generating health, economic and social problems in the affected countries and it is considered a neglected diseases making it not attractive for pharmaceutical industries. Currently available treatments use the drugs a nitrofurfurylidene-amino (Nifurtimox) and a nitroimidazole acetamide (Benznidazole). Both are not completely effective against the disease, for several reasons: on the one hand only serve during the acute stage of the disease, since they have low efficacy during the chronic phase, in the other hand these treatments have significant variations depending on the region, a consequence of the development of resistance to drugs by T. cruzi. To overcome these problems we are using natural products combined with nuclear magnetic resonance based metabolomic analysis. We could identify  the responsible compound of the trypanosomicidal activity in Baccharis trimera, this being a diterpene of the labdane type containing an aldehyde, agreeing with results obtained by the group previously where metabolites of the same nature had been described with trypanosomicidal activity in Aristeguieta glutinosa. In the present work the Baccharis trimera fractionation oriented to verified the above compound is performed using gradient of polar disolvents extractions, and the biological activity of the fractions obtained in the process is monitored by in vitro assays in the epimastigote form of T. cruzi, Tulahuen 2 strain and the 1H NMR metabolomic characterization. The results obtained confirm that the ethyl acetate Baccharis trimera fraction has an important anti-T. cruzi, and besides that the aldehyde-diterpene is not the only metabolite present in the plant, so we can also infer that we are facing a synergistic effect.

  • Open access
  • 97 Reads
Design of Novel Tubulin Polymerization Inhibitors Based on CA-4
Published: 10 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session Posters

Combretastatin A-4(CA-4), a group of polyhydroxylated stilbenes isolated from the bark of the South African tree Combretum Caffrum, is a highly effective natural tubulin-binding molecule affecting microtubule dynamics by binding to the colchicines site. Its water soluble phosphate ester (CA-4P) is under evaluation in phase 3 trials for treatment of anaplastic thyroid cancer and in phase 2 trials for non-small cell lung cancer and platinum-resistant ovarian cancer, thus stimulating significant interest in a variety of combretastatin A-4 analogues. Unfortunately, a problem have limited their use as therapeutic agents. The cis configuration is biologically active, with the trans form showing significantly inactive. The active cis double bond in CA-4 is readily converted to the more stable trans isomer during storage or metabolism by heat, light, and protic media , resulting in a dramatic decrease in antitumor activity. Thus, it is necessary to design and discover novel cis configuration inhibitors based on CA-4.