Natural Inhibitors of Mitochondrial Respiratory Chain: Therapeutic and Toxicological Implications

Total Synthesis of Caldorazole, a Potent Mitochondrial Respiratory Chain Inhibitor without Chiral Centers

“…The residue was purified by AFCS [column Yamazen Ultra Pack Si-40B (ϕ 26 mm × 300 mm); solvent hexane/EtOAc 56/ 44 (0−7 min), linear gradient elution to 35/65 (7−28 min), 35/65 (28−40 min); flow rate 20 mL/min; detection UV 254 nm] to afford alcohol S-3 (268 mg, 0.72 mmol, t R = 29−35 min, 78%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.70 (s, 1H), 5.44−5.37 (m, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.53 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.40 (q, J = 6.8 Hz, 2H), 1.98 (q, J = 6.8 Hz, 2H), 1.88 (quint, J = 6.9 Hz, 2H), 1.50 (quint, J = 6.9 Hz, 2H), 0.84 (s, 9H), −0.01 (s, 6H); 13 C{ 1 (5). To a solution of alcohol S-3 (636 mg, 1.72 mmol) in CH 2 Cl 2 (8 mL) cooled at 0 °C was added DMP (1.09 g, 2.58 mmol), and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with saturated aqueous Na 2 S 2 O 3 (10 mL).…”

“…Many natural products, including biakamides, 2 piericidin, 3 and rotenone, 4 have been reported as inhibitors of mitochondrial respiratory chain complex I. 5 Since all of these natural products have asymmetric centers, complex stereo-controlled syntheses are required for drug development inspired by them. On the other hand, caldorazole (1) is a unique natural product that exhibits potent inhibitory activity comparable to those of known inhibitors despite having no chiral centers.…”

“…Detailed biological analyses have revealed that caldorazole ( 1 ) inhibits mitochondrial respiratory chain complex I, which has recently attracted attention as a promising therapeutic target for anticancer drugs. Many natural products, including biakamides, piericidin, and rotenone, have been reported as inhibitors of mitochondrial respiratory chain complex I . Since all of these natural products have asymmetric centers, complex stereo-controlled syntheses are required for drug development inspired by them.…”