Differential Pharmacologic Properties of the Two C75 Enantiomers: (+)‐C75 Is a Strong Anorectic Drug; (−)‐C75 Has Antitumor Activity

Abstract

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identifying it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential different biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that (-)-C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

Differential in radiosensitizing potency of enantiomers of the fatty acid synthase inhibitor C75

“…However, the (−) enantiomer was more potent than the racemic mixture, whereas the (+) enantiomer had less potency than the racemic mixture in both cell lines. This is in agreement with the antitumor effect of C75 previously described by Makowski et al11 in breast and ovarian cancer cell lines, wherein the (+) enantiomer of C75 was less potent than the racemic mixture or the (−) enantiomer. Similar to the cytotoxicity assays, in clonogenic assays of PC3 cells the racemic mixtures had near identical activity, which was less than the (−) enantiomer and more than the (+) enantiomer (Figure 3).…”

“…It has previously been reported that, although C75 had a minimal effect on CPT‐1 activity, (+)‐C75‐CoA inhibited CPT‐1 to a significantly greater extent than either racemic C75‐CoA or (−)‐C75‐CoA 11. Furthermore, when injected into rats the anorectic effect of C75 was largely attributed to the presence of (+)‐C75 11.…”

“…Conversely, experiments in vitro and in rodent models demonstrated that C75 is converted to C75‐CoA 9, 10. Accumulation of C75‐CoA and malonyl‐CoA, caused by reduced FASN activity, act as signals of nutrient abundance to hypothalamic neurons, inhibiting CPT‐1 and mediating the suppression of food intake and further contributing to weight loss 11. This has led to the evaluation of drugs that inhibit FASN but do not affect CPT‐1 activity 12, 13…”

“…Radiosensitization of cancer cells was also achievable using C75 6. However, it is possible that the racemic mixture of C75 may modulate the activity of CPT‐1 activity, which is responsible for its undesirable effects on body weight and appetite in patients with cancer 11. Here we evaluated the radiosensitizing activity of enantiomers of C75 in comparison with the commonly used racemic mixture of C75.…”

(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

“…The preparation of (-)-C75 and (+)-C75 enantiomers separately was not reported until recently [13]. We have previously shown that (-)-C75 inhibits FAS activity in vitro and has cytotoxic effects on tumour cell lines, whereas (+)-C75 inhibits CPT1 in vitro and its administration to rodents produces anorexia [14].…”