Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E, E-3,5-bis(arylidene)piperid-4-ones

• Published in: European journal of medicinal chemistry Vol. 44; no. 5; pp. 2135 - 2144
• Main Authors: Makarov, Michael V., Rybalkina, Ekaterina Yu, Röschenthaler, Gerd-Volker, Short, Kurt W., Timofeeva, Tatiana V., Odinets, Irina L.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-05-2009
• Subjects: Aminophosphonates; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones; N-phosphorylalkylene-piperid-4-ones; Organophosphonates; Piperidones - chemistry; Piperidones - pharmacology; Structure-Activity Relationship; Structure–cytotoxicity–fluorescence relationship; Synthesis; Aminophosphonates; Synthesis; Structure–cytotoxicity–fluorescence relationship; N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones; N-phosphorylalkylene-piperid-4-ones
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2008.10.019

A series of
E,
E-
N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones
7a–
k was prepared via the condensation of aromatic aldehydes with ω-aminophosphonates
5a–
c and
6a,
b bearing piperidone or a protected piperidone moiety, respectively. The synthetic routes to the starting aminophosphonates
5a–
c and
6a,
b varied depending on the number of methylene groups in the alkylene chain and comprised the Kabachnik–Fields reaction (
n
=
1), the aza-Michael reaction (
n
=
2) or alkylation of 4-piperidone hydrochloride with diethyl ω-bromoalkylphosphonates under phase transfer catalysis conditions (
n
=
3,4). Phosphoryl substituted 3,5-bis(arylidene)piperid-4-ones
7b,
c,
e,
f,
h,
i,
k bearing both nitro groups and fluorine atoms in the
para-position of the arene rings possess cytotoxicity toward human carcinoma cell lines CaOv3, Scov3, PC3 and A549 in the low micromolar range while their analogues having
para-dimethylamino groups had IC
50 values greater than 50
μM. In contrast, only Me
2N-substituted phosphonates
7g,
j (
n
=
3 and 4) and the salts of Me
2N-substituted phosphonic acids
10c,
f (
n
=
2 and 3) display fluorescence.
Condensation of ω-aminophosphonates bearing piperidone or a protected piperidone moiety with aromatic aldehydes provides a convenient approach to
E,
E-
N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones possessing dark cytotoxicity towards human carcinoma cell lines CaOv3, Scov3, PC3 and A549 in the low micromolar range in the case of electron withdrawing substituents in the benzene rings and fluorescence properties for those having electron-donating groups.
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