Semisynthetic Esters of 17-Hydroxycativic Acid with in Vitro Cytotoxic Activity against Leukemia Cell Lines

A collection of sixteen semisynthetic 17-hydroxycativic acid esters with alcohols containing a tertiary amine group was evaluated for their in vitro cytotoxicity against two human cancer cell lines, THP-1 and U937, and for their effects on the cell cycle and cell death. While 17-hydroxycativic acid...

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Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2017/11/01, Vol.40(11), pp.1923-1928
Main Authors: Cavallaro, Valeria, Řezníčková, Eva, Jorda, Radek, Alza, Natalia Paola, Murray, Ana Paula, Kryštof, Vladimír
Format: Article
Language:English
Subjects:
17-hydroxycativic acid
Adenosine diphosphate
Alcohols
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antitumor activity
Apoptosis
Apoptosis - drug effects
Cancer
Caspase 3 - metabolism
Caspase 7 - metabolism
Cell cycle
Cell Cycle - drug effects
Cell death
Cell Line, Tumor
cytotoxic activity
Cytotoxicity
Diterpenes
Diterpenes - chemistry
Diterpenes - pharmacology
diterpenoid
Esters
Esters - chemistry
Esters - pharmacology
human cancer cell
Humans
Inhibitory Concentration 50
Leukemia
Leukemia - drug therapy
Poly (ADP-Ribose) Polymerase-1 - metabolism
Poly(ADP-ribose) polymerase
Ribose
Structure-Activity Relationship
Tumor cell lines
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Summary:A collection of sixteen semisynthetic 17-hydroxycativic acid esters with alcohols containing a tertiary amine group was evaluated for their in vitro cytotoxicity against two human cancer cell lines, THP-1 and U937, and for their effects on the cell cycle and cell death. While 17-hydroxycativic acid itself is not cytotoxic, all the esters displayed cytotoxic activity, with 50% growth inhibition (GI50) values ranging between 3.2 and 23.1 µM. In general, the most potent compounds in both cell lines were esters with four carbon long alcohol residues. There was no clear relationship between the identity of the terminal secondary amine and the activity of the compound. Experiments using the 6-(pyrrolidin-1-yl)pentyl ester, 2c, revealed that this compound activates caspases-3/7 and causes poly(ADP-ribose)polymerase 1 (PARP-1) fragmentation in THP-1 and U937 cells, indicating the induction of apoptotic cell death. These results suggest that further investigation into the anticancer activity of diterpene derivatives and other labdane diterpenes may be fruitful.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b17-00477