Working Group Progress Report Bioscience-related topic

1. PhoSciNet CM0802 Working Group Progress Report Bioscience-related topic Prof. Dr. Paweł Kafarski WG3 Chair PhoSciNet Final Conference, Regensburg, 18-20 March 2013

2. WG3 Group Leaders 2012 PhoSciNet 2 1 2 2 1 1 1 1 3 1 1 2 Israel 1 1 2

3. PhoSciNet WG3 Outputs Paweł Kafarski Anna-Marie Caminade • Pertinent journal publications by WG3 members: 143 in total 10 PhoSciNet acknowledged 10 PhoSciNet collaborations 4 books (overlapping with other WGs) 6 book chapters (as above) Eli Breuer Tarik Eren Giuseppe Forlani Declan Gilheany Christian Hackenberger Peter Hermann Lee Higham Mark Johnson László Kollár Marc Lecouvey Maurizio Peruzzini Andrew Philips Jean-Luc Pirat Manuel Romerosa Nievas Luminita Silaghi-Dumitrescu John Derek Woollins Jouko Vepsäläinen 3

4. Bioactive molecules as potential drugs as potential agrochemicals WG1 Biologically active dendrimers phosphonate-ended ones ammonium ended-ones Functionalization of biological molecules WG2 steroids alkaloids peptides and proteins Organometallic anticancer agents water-solouble ones WG4 PhoSciNet WG2 General Objectives Diagnostics & drug delivery systems 4

5. PhoSciNet WG3 Highlights: Bioactive molecules Glioblastoma, is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. The glycomimetic family, named phostine interfere with glycosylation inhibiting the N-acetyl glycosyl transferase V (GnT-V). They selectively inhibit HuGBM cells migration, invasion and neurosphere formation as well as cancer cellsproliferation in vivo and in vitro more than 150 molecules synthesized 5 Pirat, Virieux, Lecouvey

6. PhoSciNet WG3 Highlights: Bioactive molecules Ureolytic bacteria cause infections of the urinary tract (most common pyelonephritis, stone formation - 15-20% of all urinary stones) or gastric disorders (gastritis, ulceration, gastric carcinoma). Urease [EC 3.5.1.5] catalyses hydrolytic decomposition of urea into ammonium and carbamate Kafarski 6

7. PhoSciNet WG3 Highlights: Bioactive molecules Meningitis is inflammation of the protective membranes covering the brain and spinal cord. Neisseria meningitides is the main causative agent of this disease.To explore the possibility of neutral aminopeptidase being a potential drug target for inhibition and development of novel therapeutic agents, the specificity of the S1 and S1' binding sites was explored using an integrated approach by using an extensive library consisting of over 100 fluorogenic substrates. Kafarski Malaria is a mosquito-borne infectious diseasea of humans and other animals caused by protists of the genus Plasmodium. It begins with a bite from an infected female mosquito, which introduces the protists through saliva into the circulatory system. In the blood, the protists travel to the liver to mature and reproduce. Malaria kills 3 millions peaople annualy. Computer-aided methods were used by for rational design of inhibitors of Plasmodium falciparum M1 neutral aminopeptide, an enzyme vital for pathogenesis and development of malaria. Based on this approach effective inhibitors were synthesised and found to be effective against five malaria models in rats. 7

8. PhoSciNet WG3 Highlights: Bioactive molecules 1-Deoxy-D-xylose-5-phosphate reductoisomerase catalyzes the first committed step in the mevalonate-independent isopentenyl diphosphate biosynthetic pathway and is a potential drug target in some pathogenic bacteria, including Mycobacterium tuberculosis. Synthesis of four types of targets bearing a phosphanyl-phosphonic acid motif as the common core for the inhibition of this enzyme was undertaken 8 Pirat, Virieux

9. PhoSciNet WG3 Highlights: Bioactive molecules Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Their inhibitors are considered as potential anticancer agents. Four classes of such inhibitors have been synthesized and evaluated. Breuer 9

10. WG3 Highlights: Bioactive molecules PhoSciNet The erosion of the cartilage lining the joints is a hallmark of osteoarthritis an extremely painfull disease of undefined origin. First generation dendrimer ended by azabisphosphonic salts is able to cure mice which suffer from a rheumatoid arthritis-like disease. Caminade 100% remission for all animals joint: cartilage erosion no synovial membrane 10

11. PhoSciNet WG3 Highlights: Bioactive molecules Alzheimer disease, is the most common form of dementia. Amyloid plaques are deposits found in the brains of patients with Alzheimer's disease. Their formation and role has not been yet well understood. Studies on the role of phosphatases and phosphorylation in promoting formation of amyloid were performed using short peptide model system. These studies may be treated as preliminary ones devoted to better understanding the molecular mode of Alzheimer and may form a platform for the drug design. Hackenberger 11

12. PhoSciNet WG3 Highlights: Bioactive molecules GS 9131 (Gilead) is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. It is a prodrug, which slowly release real GS 9148 inhibitor. The creative syntheses of this drug have been undertaken. Gilheany 12

13. PhoSciNet WG3 Highlights: Functionalisation of skeletons of biological importance Protocol in protein bioengineering allowing the site-specific incorporation of chemical reporter rmoieties was elaborated based on Staudinger-phosphonite reaction. Subsequently, these functional groups can be chemoselectively transformed to decorateproteins with charged and oversized functional units. Hackenberg

14. PhoSciNet WG3 Highlights: Functionalisation of skeletons of biological importance Kollár 14

15. WG3 Highlights: Functionalisation of skeletons of biological importance PhoSciNet The quality of therapeutically administered glycoproteins can be efficiently improved by the incorporation of chemically functionalized monosaccharides into their glycan moieties, a process denoted as metabolic oligosaccharide engineering. The studies were undetaken whether the biosynthetic machinery for sialic acids also tolerates reactive analogues of substrate – N-acetylmannosamine. Metabolic incorporation of synthetically derived N-acetyl-4-azido-4-deoxymannosa-mine into glycans of mammalian cells and zebrafish larvae preserves the bioorthogonal functionality of its azido group for subsequent labeling with biophysical probes. Hackenberg 15

16. WG3 Highlights: Water-soluble organometallic complexes PhoSciNet The cytotoxic effect is modulated both by the central metal and by the organoarsenic ligand Cellular growth inhibitions in hepatic cells after 24 h treatment with platinum and palladium complexes 1–4. Hey-Hawkins Silaghi-Dumitrescu 16

17. WG3 Highlights: Water-soluble organometallic complexes PhoSciNet Romerosa 17

18. PhoSciNet WG3 Highlights: Drug delivery Glaucoma is an eye disease in which the optic nerve is damaged in a characteristic pattern. This can permanently damage vision in the affected eye(s) and lead to blindness if left untreated. pplication of organophosphorus dendrimers resulted in the proposition of a new delivery system for carteolol,ocular drug against glaucoma. This system enables to reach higher concentration of the drug and avoid eye irritation upon its application. Studies carried out on rabbits are highly promising. Caminade 18

19. PhoSciNet WG3 Highlights: Drug delivery Phophorus ionic micelles and triblock amphiphilic polymer capsules for targeted drug delivery and imaging Eren 19

20. PhoSciNet WG3 Highlights: Drug delivery Aminophosphonate-functionalized nanoparticles Kafarski

21. γ-Fe2O3 transmission 2,0 Control 1,5 Tumor volume (cm3) 1,0 0,5 fluorescence 0,0 0 1 2 3 4 5 6 PhoSciNet WG3 Highlights: Drug delivery combined with diagnostics Theranostic is a proposed process of diagnostic therapy for individual patients - to test them for possible reaction to taking a new medication and to tailor a treatment for them based on the test results. It is element of personalized medicine. In this case it is multimodal system, which combines magnetic targeting of therapeutic agents with both magnetic resonance and fluorescence imaging into one system - neridronate transport to MDA-MB-231 human breast cancer cells Lecouvey 21

22. MRI Non labeled islets - right Labeled islets - left PhoSciNet WG3 Highlights: Drug delivery combined with diagnostics Gd3+-DOTA monoamide Rhodamine B derivative ~3000 Gd3+-complexes/particle ~600 molecules/particle Langerhans islets Hermann 22

23. PhoSciNet WG3 Highlights: Diagnostics Phosphorus dendrimers linked to an organic fluorophore as core, specially engineered for possessing two-photon absorption (TPA) properties was used for intracardiac injection in a Xenopus tadpole, allowing imaging of the blood vessels of the tail. Xenopus laevis Caminade 23

24. PhoSciNet WG3 Highlights: Diagnostics High selectivity for complexation of68Ga3+ over other metal ion as Zn2+ (decay product) or Fe3+ (the most common impurity) β-CD nude mouse tumor xenografts. Left: 68Ga-NOPO–RGDfK (M21 human melanoma); right: 68Ga-NOPO–NOC (AR42J rat pancreas carcinoma) Hermann 24

25. PhoSciNet WG3 Highlights: Diagnostics bone scanning agents linked to a γ-emitting technetium isotope Vepsäläinen 25 99mTc labelled partial ester

26. Paweł Kafarski WG3 Chair Wrocław University of Technology Poland COST Action CM0802 www.phoscinet.org 26