The research interests of the Sarli lab lie in the fields of organic chemistry and chemical biology. Many new biological and medicinal advances were facilitated by probing biological systems at the molecular level using chemical tools. In particular, our laboratory is focused on the design and synthesis of small molecules and natural products as modulators of clinically relevant proteins for the study of biological processes and the development of novel therapeutics.
Synthesis and biological evaluation of a Platinum(II)-c(RGDyK) conjugate for integrin-targeted photodynamic therapy
Chatzisideri T, Thysiadis S, Katsamakas S, Dalezis P, Sigala I, Lazarides T, Nikolakaki E, Trafalis D, Gederaas OA, Lindgren M, Sarli V
A cancer-targeting conjugate 4 of a cyclometalated [N,C,N-Pt(II)] complex bearing a N^C^N 1,3-di(2- pyridyl)-benzene with c(RGDyK) peptide as guiding molecule was designed and synthesized for realtime drug delivery monitoring in cancer cells and photodynamic therapy (PDT). This conjugate demonstrates a mild cytostatic effect to six cancer cell lines expressing integrins at different extent, while possessing promising features for PDT. Conjugate 4 demonstrated rapid cell uptake by receptor-mediated endocytosis and efficient generation of 1O2 upon irradiation. Incubation of rat bladder cancer cells AY27 with conjugate 4 (50 mМ) prior to blue light exposure (5 min) resulted in significant reduction (50%) of cell survival compared to control cells as measured by MTT assay post 24 h after treatment.
Thysiadis S, Katsamakas S, Dalezis P, Chatzisideri T, Trafalis D, Sarli V. Future Med Chem. 2017, 9(18), 2181-2196.
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.
Trafalis DT, Polonifi A, Dalezis P, Nikoleousakos N, Katsamakas S, Sarli V, Chem Biol Drug Des. 2017, 90(5):854-866.
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.
RGD-mediated delivery of small-molecule drugs
Katsamakas S, Chatzisideri T, Thysiadis S, Sarli V, Future Medicinal Chemistry, 2017, 9(6): 579-604
Conjugates of cytotoxic agents with RGD peptides 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.
Lynamicin D an Antimicrobial Natural Product Affects Splicing by Inducing the Expression of SR Protein Kinase 1
Sigala I, Ganidis G, Thysiadis S, Zografos AL, Giannakouros T, Sarli V, Nikolakaki E. Bioorg Med Chem. 2017, 25(5), 1622-1629.
The first total synthesis of the antimicrobial natural product lynamicin D has been developed using a Suzuki coupling to construct the bisindole pyrrole skeleton. An evaluation of the biological activity of lynamicin D reveals that it has a minor effect on cell viability but it can modulate splicing of pre-mRNAs. We provide evidence that this effect is mainly due to the ability of lynamicin D to alter the levels of SRPK1, the key kinase involved in both constitutive and alternative splicing.
Trafalis D, Geromichalou E, Dalezis P, Nikoleousakos N,Sarli V, Steroids, 2016, 115: 1-8.\
Alkylating agents are still nowadays one of the most important classes of cytotoxic drugs, which display a wide range of therapeutic use for the treatment of various cancers. We have synthesized and tested four hybrid homo-azasteroidal alkylating esters for antileukemic activity against five sensitive to alkylating agents human leukemia cell lines in vitro and in vivo against P388 murine leukemia. Comparatively, melphalan and 3-(4-(bis(2-chloroethyl)amino)phenoxy)propanoic acid (POPAM) were also examined. All the homo-aza-steroidal alkylators showed relatively lower acute toxicity, very promising and prominent antileukemic activity both in vitro and in vivo.
Mpousis S, Thysiadis S, Avramidis N, Katsamakas S, Efthimiopoulos S, Sarli V. Eur J Med Chem. 2016, 108:28-38.
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.
Savvas Thysiadis, Spyros Mpousis, Nicolaos Avramidis, Sotirios Katsamakas, Athanasios Balomenos, Rosaria Remelli, Spyros Efthimiopoulos, Vasiliki Sarli, Bioorg Med Chem. 2016, 24(5):1014-22
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.
Gold-catalyzed spiro-N,O-ketal synthesis
Grammatikopoulou M, Thysiadis S, Sarli V, Org Biomol Chem. 2015, 13, 1169.
An efficient method for the synthesis of spiro-N,O-ketals with 5- and 6-membered rings was developed via a gold-catalyzed spiroamidoketalization of alkynyl amidoalcohols under mild conditions. This methodology has been successfully applied to the synthesis of a spiro-N,O-ketal analogue of marineosin A.
A Chatzimpaloglou , M Kolosov , TK Eckols , DJ Tweardy, Sarli V, J Org Chem. 2014, 79, 4043.
The signal transducer and activator of transcription 3 (STAT3) has been validated as a suitable target for cancer therapy. Recent evidence by our group and others has shown that the phaeosphaerides act as inhibitors of the STAT3 pathway. An efficient synthetic sequence to phaeosphaeride 1a has been previously disclosed. In this work, the first total synthesis of (±)-phaeosphaeride B (1d) and the unnatural phaeosphaeride 1b is reported. Additionally, the biological activities of 1a were investigated. (6S,7S,8S)-1a inhibited granulocyte colony-stimulating factor (GCSF)-stimulated phosphorylation of STAT1, STAT3 and STAT5A and IL-6 stimulated nuclear translocation of STAT3 Alpha and Beta. In an SPR-based assay, (6S,7S,8S)-1a showed essentially no ability to inhibit binding of STAT3 to its immobilized phosphotyrosylpeptide ligand (IC50>1000 μM). Thus, (6S,7S,8S)-1a does not interact with the SH2 binding domain of STAT3 and is likely an upstream inhibitor of a Janus kinase in the JAK/STAT pathway.
Synthetic and Biological Studies of Phaeosphaerides
An efficient synthetic sequence to (±)-phaeosphaeride B (1d) and the unnatural phaeosphaeride 1b is reported. (6S,7S,8S)-1a and (6R,7S,8S)-1b inhibited granulocyte colony-stimulating factor (GCSF)-stimulated phosphorylation of STAT1, STAT3, and STAT5 and IL-6-stimulated nuclear translocation of STAT3 alpha. In an SPR-based assay, (6S,7S,8S)-1a and (6R,7S,8S)-1b showed minimal ability to inhibit binding of STAT3 to its immobilized phosphotyrosylpeptide ligand (IC50 > 100 μM). Thus, (6S,7S,8S)-1a and (6R,7S,8S)-1b are likely upstream inhibitors of a kinase in the STAT signaling pathway and do not act through the inhibition of STAT3 dimerization by the blocking of the SH2 binding domain.
Total Synthesis of (±)-Marinopyrrole A via Copper-Mediated N-Arylation
Kanakis AA, Sarli V, Org Lett. 2010 Nov 5;12(21):4872-5.
Marinopyrrole A (1) was extracted as single atropo-enantiomer in 2008 from the marine Streptomyces strain CNQ-418. Interestingly, when screened for biological activity, marinopyrrole A exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cytotoxicity against human cancer cells. We synthesized the racemic form of the marinopyrrole A by a copper-mediated N-arylation process under microwave irradiation.
UA62784 is a cytotoxic inhibitor of microtubules, not CENP-E
S Tcherniuk, S Deshayes, V Sarli, G Divita, A Abrieu, , Chem Biol. 2011, 18, 631
A recent screen for compounds that selectively targeted pancreatic cancer cells isolated UA62784. We found that UA62784 inhibits microtubule polymerization in vitro. UA62784 interacts with tubulin dimers ten times more potently than colchicine, vinblastine, or nocodazole. Competition experiments revealed that UA62784 interacts with tubulin at or near the colchicine-binding site. Nanomolar doses of UA62784 promote the accumulation ofmammalian cells in mitosis, due to aberrant mitotic spindles, as shown by immunofluorescence and live cell imaging. Treatment of cancerous cell lines with UA62784 is lethal, following activation of apoptosis signaling. By monitoring mitotic spindle perturbations and apoptosis, we found that the effects of UA62784 and of some known microtubule-depolymerizing drugs are additive. Finally, high content screening of H2B-GFP HeLa cells revealed that low doses of UA62784 and vinblastine potentiate each other to inhibit proliferation.
Recent Advances of Kinesin Motor Inhibitors and their Clinical Progress
A Voultsiadou, V Sarli,, Rev Recent Clin Trials, 2011, 6, 271.
Antimitotic chemotherapy remains the most effective approach to treat a variety of human neoplasms. Since the discovery of tubulin-targeting agents, vinca alkaloids and the taxanes including paclitaxel and docetaxel are used clinicallyto treat several solid tumors of the head and neck, breast, lung, ovary, and bladder. Despite the preclinical and clinical success of tubulin-targeting agents, the ability of tumors to develop an acquired resistance to drugs used for treatment and neurotoxicity severely limited their long-term effectiveness to cancer cure. Lately, advances in antimitotic treatments led to the identification of novel mitosis-specific agents that are expected to show higher selectivity and less cytotoxicity compared to known antimitotics. This review focuses on the progress of kinesin motor inhibitors that target proteins that function predominantly in mitosis.