Synthesis and in vitro cytotoxicity of cross-conjugated prostaglandin A and J series and their hydroxy derivatives

Abstract

The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 μM. Moreover, the C7-hydroxy derivative of NEPP11 displayed high cytotoxic selectivity between cancer cell lines and normal human cells. On the other hand, the J-type prostaglandin analogue of NEPP11 and its C13-hydroxy derivatives were much less toxic or nontoxic against the cancer and normal cells at concentrations up to 1 mM.

Synthesis of Enantiomerically Pure Stereomers of Rosaprostol

“…Recently, in the context of our research program aimed at the development of new methods for the synthesis of bioactive prostanoids and investigation of stereostructure–activity relationships in this class of compounds, we have reported the synthesis and cytotoxicity of enantiomeric 13,14-dihydro-15-deoxy-Δ 7 -PGA 1 methyl esters ( 2 ) (TEI-9826) and structurally related NEPP-11 3 and its J-type analogue 4 (Scheme ).…”

A novel route to a chiral building block for the preparation of cyclopentenyl carbocyclic nucleosides. Synthesis and anticancer activity of enantiomeric neplanocins A

“…50 These chiral cyclopentenone building blocks were prepared in two steps from meso-tartaric acid and subsequently converted in a ve-step reaction sequence into enantiomeric alcohols (À)-3b and (+)-3b (Scheme 3). Although phosphonates 4 and 5 were also successfully applied in the syntheses of both enantiomers of anticancer cyclopentenone prostaglandin analogue TEI-9826 51 and the two cross-conjugated derivatives of prostaglandin A and J series with neurotrophic activity, 52 their preparation suffers from a low diastereoselectivity of the cyclopentenone ring formation and difficult separation.…”

Concise Synthesis of a New Chiral Cyclopentenone Building Block for Prostaglandins and their Derivatives

“…In the frame of our research program aimed at the invention and development of general methods for the synthesis of bioactive cyclopentenones and cyclopentanones using phosphonate reagents, the diastereoisomeric camphor protected 3‐[(dimethoxyphosphoryl)methyl]‐4,5‐dihydroxycyclopent‐2‐enones 3 have emerged as particularly useful starting materials in the synthesis of various chiral cyclopentenone and cyclopentanone derivatives. The utility of these blocks was demonstrated, among others, via the synthesis of anticancer cyclopentenone PG derivatives (enantiomers of TEI‐9826, NEPP‐11 and iso ‐NEPP‐11) and two enantiomerically pure stereoisomers of rosaprostol – an antiulcer drug …”