Anticancer activity of koningic acid and semisynthetic derivatives.
A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential.
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France. Electronic address: nicolas.rahier@pierre-fabre.com.
Nicolas J
NJ
Rahier
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
Nicolas
N
Molinier
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
Christophe
C
Long
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Sunil Kumar
SK
Deshmukh
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Abhijeet S
AS
Kate
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Prafull
P
Ranadive
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Shilpa Amit
SA
Verekar
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Mangesh
M
Jiotode
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Rahul R
RR
Lavhale
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Pradipta
P
Tokdar
Piramal Enterprises Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon East, Mumbai, Maharashtra 400 063, India.
Arun
A
Balakrishnan
Antitumoral Pharmacology Unit, Centre Oscar Lambret, Inserm U908, BP 307, 59020 Lille cedex, France.
Samuel
S
Meignan
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
Céline
C
Robichon
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
Bruno
B
Gomes
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
Yannick
Y
Aussagues
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
Arnaud
A
Samson
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France.
François
F
Sautel
Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien-BP 13562, 31035 Toulouse cedex 1, France. Electronic address: christian.bailly@pierre-fabre.com.
Christian
C
Bailly
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005285:Fermentation; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014242:Trichoderma / Q000737:chemistry / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D012717:Sesquiterpenes; C027285:heptelidic acid
Cancer; GAPDH; Glycolysis; Koningic acid; Natural products; Semisynthesis