PMID- 10377217
OWN - NLM
STAT- MEDLINE
DCOM- 19990708
LR  - 20221207
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 42
IP  - 12
DP  - 1999 Jun 17
TI  - Phthalein derivatives as a new tool for selectivity in thymidylate synthase 
      inhibition.
PG  - 2112-24
AB  - A new set of phthalein derivatives stemming from the lead compound, 
      phenolphthalein, were designed to specifically complement structural features of 
      a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the 
      human TS (hTS) enzyme. The new compounds were screened for their activity and 
      their specificity against TS enzymes from different species, namely, L. casei 
      (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human 
      thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the 
      compounds against LcTS were determined, and inhibition factors (IF, ratio between 
      the initial rates of the enzymatic reaction in the presence and absence of each 
      inhibitor) against each of the four TS species were measured. A strong 
      correlation was found between the two activity parameters, IF and Ki, and 
      therefore the simpler IF was used as a screening factor in order to accelerate 
      biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial 
      inhibition of LcTS while remaining largely inactive against hTS, illustrating for 
      the first time remarkable species specificity among TSs. Due to sequence homology 
      between the enzymes, several compounds also showed high activity and specificity 
      for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 
      3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 
      microM) while remaining inactive in the hTS assay at the maximum solubility 
      concentration of the compound (200 microM). In cell culture assays most of the 
      compounds were found to be noncytotoxic to human cell lines but were cytotoxic 
      against several species of Gram-positive bacteria. These results are consistent 
      with the enzymatic assays. Intriguingly, several compounds also had selective 
      activity against Cr. neoformans in cell culture assay. In general, the most 
      active and selective compounds against the Gram-positive bacteria were those 
      designed and found in the enzyme assay to be specific for LcTS versus hTS. The 
      original lead compound was least selective against most of the cell lines tested. 
      To our knowledge these compounds are the first TS inhibitors selective for 
      bacterial TS with respect to hTS.
FAU - Costi, P M
AU  - Costi PM
AD  - Dipartimento Scienze Farmaceutiche and Dipartimento Scienze Chimiche, Universita 
      di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
FAU - Rinaldi, M
AU  - Rinaldi M
FAU - Tondi, D
AU  - Tondi D
FAU - Pecorari, P
AU  - Pecorari P
FAU - Barlocco, D
AU  - Barlocco D
FAU - Ghelli, S
AU  - Ghelli S
FAU - Stroud, R M
AU  - Stroud RM
FAU - Santi, D V
AU  - Santi DV
FAU - Stout, T J
AU  - Stout TJ
FAU - Musiu, C
AU  - Musiu C
FAU - Marangiu, E M
AU  - Marangiu EM
FAU - Pani, A
AU  - Pani A
FAU - Congiu, D
AU  - Congiu D
FAU - Loi, G A
AU  - Loi GA
FAU - La Colla, P
AU  - La Colla P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 
      (3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H,3H-naphtho(1,8-c,d)pyran-1-one)
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Chlorophenols)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 6QK969R2IF (Phenolphthalein)
RN  - EC 2.1.1.45 (Thymidylate Synthase)
SB  - IM
MH  - Anti-Bacterial Agents
MH  - Anti-Infective Agents/*chemical synthesis/chemistry/pharmacology
MH  - Cell Line
MH  - Chlorophenols/*chemical synthesis/chemistry/pharmacology
MH  - Chromones/*chemical synthesis/chemistry/pharmacology
MH  - Cryptococcus neoformans/enzymology
MH  - Crystallography, X-Ray
MH  - Drug Design
MH  - Enzyme Inhibitors/*chemical synthesis/chemistry/pharmacology
MH  - Gram-Positive Bacteria/drug effects
MH  - Humans
MH  - Lacticaseibacillus casei/enzymology
MH  - Models, Molecular
MH  - Phenolphthalein/chemistry
MH  - Pneumocystis/enzymology
MH  - Species Specificity
MH  - Structure-Activity Relationship
MH  - Thymidylate Synthase/*antagonists & inhibitors
EDAT- 1999/06/23 00:00
MHDA- 1999/06/23 00:01
CRDT- 1999/06/23 00:00
PHST- 1999/06/23 00:00 [pubmed]
PHST- 1999/06/23 00:01 [medline]
PHST- 1999/06/23 00:00 [entrez]
AID - jm9900016 [pii]
AID - 10.1021/jm9900016 [doi]
PST - ppublish
SO  - J Med Chem. 1999 Jun 17;42(12):2112-24. doi: 10.1021/jm9900016.