title: In silico/in vitro study of hybrid D-modified steroidal alkylator anticancer activity using uridine phosphorylase as target protein.
abstract: BACKGROUND
  In order to reduce toxicity and to enhance anticancer activity of nitrogen mustards, three hybrid steroidal esters were synthesized and tested in vitro against human pancreatic cancer cells expressing uridine phosphorylase (UPase). The inhibition potency against a target protein implicated in the chemotherapy of solid tumors, such as UPase, is of fundamental importance in the design and synthesis of new anticancer drugs.
  
  
  METHODS
  MTT colorimetric assay and molecular docking were employed for the in vitro and in silico drug evaluation, respectively.
  
  
  RESULTS
  A difference in cell sensitivity was found, which followed the known different UPase expression in the cell lines. Molecular docking studies on UPase protein, revealed the tested compounds to be bound to the binding cavity of the protein, with different affinity. Between the two D-modified compounds, the D-homo-aza (lactam)-hybrid compound (C2) was found to interact with the protein in a more efficient way.
  
  
  CONCLUSIONS
  The molecular docking data were in accordance with the in vitro results, where the lactam steroid alkylator showed significantly higher cytostatic and cytotoxic activity than the non-D-modified compounds, which also correlated with the level of UPase expression in the pancreatic cancer cells.
authors.affiliation: Head, Laboratory of Cell Culture, Molecular Modeling and Drug Design, Symeonidion Research Center, Theagenion Cancer Hospital, 2, Al. Symeonidi Str., 54007, Thessaloniki, Greece. geromchem@yahoo.gr
authors.forename: George D
authors.initials: GD
authors.lastname: Geromichalos
authors.forename: Elena
authors.initials: E
authors.lastname: Geromichalou
authors.forename: Charalambos
authors.initials: C
authors.lastname: Camoutsis
authors.forename: Michael
authors.initials: M
authors.lastname: Kontos
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Dalezis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papageorgiou
authors.forename: Anastasios A
authors.initials: AA
authors.lastname: Grivas
authors.forename: Christos
authors.initials: C
authors.lastname: Tsigris
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Trafalis
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics; D013889:Thiouracil / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C412508:5-phenylthioacyclouridine; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D008024:Ligands; D009363:Neoplasm Proteins; D013256:Steroids; D013889:Thiouracil; D014543:Uridine Phosphorylase; D005472:Fluorouracil