Sotirios Katsamakas

RGD-mediated delivery of small-molecule drugs

Conjugates of cytotoxic agents with RGD peptides (Arg-Gly-Asp) addressed to ανβ3, α5β1 and ανβ6 integrin receptors overexpressed by cancer cells, have recently gained attention as potential selective anticancer chemotherapeutics. In this review, the design and the development of RGD conjugates coupled to different small molecules including known cytotoxic drugs and natural products will be discussed.

Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies.

In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396.

Considering Autotaxin Inhibitors in Terms of 2D-QSAR and 3D-Mapping- Review and Evaluation

The potential role of Autotaxin (ATX) in physiological and pathological processes turned it in an attractive drug target for pharmacological therapeutic development. However, potent and selective non-lipid as well lipid inhibitors of ATX are currently not available as drugs. In this paper we tried to review all the known progress on ATX inhibition using two dimensional (2D)-Quantitative Structure Activity Relationship (QSAR) and three dimensional (3D) mapping techniques. Furthermore, we tried to compare and extract conclusions analyzing with 3D mapping techniques vastly diverse structures of non-lipid ATX inhibitors which have been reported in patents. McGowans Volume (MgVol) molar volume and Molar Refractivity (MR) of substituents seems to govern the ATX inhibition. 3D-mapping results point to the role of steric properties (Volume and Polar Surface Area-PSA). Steric factors are obviously important. The role of hydrophilicity was also highlighted. Electronic parameters are not found to be present.

Advances of Phenoxazines: Synthesis, Reactivity and Their Medicinal Applications

Phenoxazines are an important class of heterocycles, which are emerging in the field of medicinal chemistry. They exhibit numerous biological activities, including antiviral, anticancer, anti-Alzheimer, antidiabetic, antioxidant, anti-inflammatory, antibiotic and many more. The present review focuses on the chemistry along with the medicinal applications of the phenoxazine moiety, in order to provide a greater insight for the development of future phenoxazine therapeutics.

Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: Synthesis, biological evaluation and structure–activity relationships

Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of β-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396.

Novel c(RGDyK)-based conjugates of POPAM and 5-fluorouracil for integrin-targeted cancer therapy

AIM Alkylating agents and antimetabolites are cytotoxic drugs commonly used in cancer treatment. These medications are often associated with serious side effects on normal tissues and organs. METHODOLOGY To improve the pharmacological profile of the alkylating agent POPAM and the antimetabolite 5-fluorouracil, novel integrin-targeted delivery systems based on c(RGDyK) were successfully synthesized. The new conjugates were tested in vitro against different cancer cells such as PC3, SKOV3, A549, MCF7 and MBA-MB-321. RESULTS & CONCLUSION The c(RGDyK) conjugates of POPAM demonstrated better inhibitory effects and selectivity compared with c(RGDyK) and POPAM. The c(RGDyK) conjugates of 5-FUA demonstrated diverse inhibitory effects compared with c(RGDyK) and 5-FUA related to the levels of integrin expression, the conjugate stability and sensitivity of cancer cells to 5-FUA.

Targeting on Poly (ADP-ribose) polymerase activity with DNA damaging hybrid lactam-steroid alkylators in wild type and BRCA1 mutated ovarian cancer cells

Conjugated lactam‐steroid alkylators (LSA) have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemjournalapy. Hybrid LSA combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSA that generate excellent anticancer activity against UWB1.289 and UWB1.289 + BRCA1 human ovarian cancer cell lines. Both UWB1.289 and UWB1.289 + BRCA1 cells carry mutations in the tumor suppressor gene TP53 while UWB1.289 cell line carries a germline BRCA1 mutation. In vitro, in vivo, and in silico, experimental methods were utilized to determine the poly(ADP‐ribose) polymerases (PARPs) activity and mRNA transcription, DNA damage, cytostatic and cytotoxic effects, and virtual molecular interactions, in order to study the molecular mechanisms of activity of the tested LSA. LSA produce anticancer activity through dual action by combining the direct induction of cellular DNA damage with the inhibition of PARP activity and consecutive DNA repair activity. BRCA1‐mutated UWB1.289 ovarian cancer cells with defective PARP‐oriented repair mechanism show significantly higher sensitivity to these agents. Combined drug effect on DNA damage and repair is a novel approach in cancer therapeutics.

Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design

Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one. The presented results are acceptable and could be used in screening as an active negative filter for boron compounds. The hydroxyl groups of amino acids are bonded with the inhibitor’s boron atom, converting its hybridization to sp3.

Design and synthesis of gallocyanine inhibitors of DKK1/LRP6 interactions for treatment of Alzheimer’s disease

Based on NCI8642, a series of gallocyanine derivatives was synthesized with modifications of the substituent groups in position 1, 2 and 4 of the phenoxazinone scaffold. The effectiveness of gallocyanines to inhibit DKK1/LRP6 interactions and Tau phosphorylation induced by prostaglandin J2 and DKK1 was elucidated by both experimental data and molecular docking simulations. Bis-alkylated with flexible alkyl ester groups on C1 and bis-benzyl gallocyanines provided the most active inhibitors, while amino derivatives on C2 of NCI8642 that have alkoxy or benzyloxy substituents on C4, were less active. Furthermore, it is shown that treating of SHSY5Y cells with NCI8642 derivatives activates Wnt signaling and increases the levels of pGSK3β kinase and β-catenin.

CCDC 1435966: Experimental Crystal Structure Determination

Related Article: Emel Pelit, Kosmas Oikonomou, Melek Gul, Dimitra Georgiou, Slawomir Szafert, Sotirios Katsamakas, Dimitra Hadjipavlou-Litina, Yiannis Elemes|2017|Comptes Rendus Chimie|20|424|doi:10.1016/j.crci.2016.05.024