Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid

Abstract

Structural modifications at the pyrimidine ring and at the C9,N10-bridge region of the thymidylate synthase (TS) inhibitors N10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.

Efficient Copper‐Catalyzed Synthesis of Poly‐N‐Heterocycles Containing Amino Acid Residues

“…Reaction of 2-bromo-N-phenylbenzamide (4) with malononitrile (2 b) to lead to 3-amino-1,2-dihydro-1-oxo-2-phenylisoquinoline-4-carbonitrile (5).…”

An efficient total synthesis of ruprechstyril fromRuprechtia tangarana

“…Substituted isoquinolones are orally effective antagonists of receptors 5-HT 3 (Matsui et al, 1992), thymidylate synthase inhibitors (Li et al, 1991), human tumour necrosis factor inhibitors and tachykinin receptors (Chao et al, 1999).…”

Synthesis, Characterization, and Physical Properties of a Conjugated Heteroacene: 2‐Methyl‐1,4,6,7,8,9‐hexaphenylbenz(g)isoquinolin‐3(2H)‐one (BIQ)

“…Generally, quinolinones and their derivatives contain many biologically active alkaloids and can serve as bases in nucleosides or building units in the synthesis of many alkaloids. [11] Many methods, which are very important in synthetic and medicinal chemistry, have been developed. [12] However, in our research, isoquinolinones 2, which are different from biologically active quinolinones, are a family of conjugated heterocyclic compounds.…”