Synthesis of Novel Rhinacanthins and Related Anticancer Naphthoquinone Esters

Abstract

Rhinacanthin-M, -N and -Q, natural products isolated from the medicinal plant Rhinacanthus nasutus, and 39 novel naphthoquinone esters have been synthesized in excellent yield by esterification of naphthoquinone-3-(propan-3'-ols) with benzoic or naphthoic acids. Almost all the naphthoquinone esters that contain a C-3 hydroxy group showed significant cytotoxicities against KB, HeLa, and HepG2 cell lines. In contrast, ester derivatives lacking the C-3 hydroxy group were inactive to the cancer cell lines. Two methyl substituents on the C-2' of propyl chain conferred more potent cytotoxicity than when there is only one or no methyl group. Naphthoate esters exhibited greater cytotoxicity than benzoate esters. Computer modeling has been done to obtain a first look at the mode of action in connection with these observations.

Synthesis and Anticancer Evaluation of Naphthoquinone Esters with 2′-Cyclopentyl and 2′-Cyclohexyl Substituents

“…was less potent than 2 0 ,2 0 -dimethyl one (6d) (IC 50 ¼ 1:59 AE 0:37 mM). 1) With similar evaluation for the HeLa and HepG 2 cancer cell lines, the 2 0 ,2 0 -dimethyl naphthoquinone esters (5d and 6d) showed stronger activity than the 2 0 -cyclopentyl (7 and 10) and 2 0 -cyclohexyl (13 and 16) esters ( Table 2).…”

“…Chemistry Naphthoquinone alcohols 32 and 33 were synthesized in nine steps (Scheme 1), starting from 1-hydroxy-2-naphthoic acid, 1) by alkylating naphthyl methyl bromide 19 with cyclopentyl 20 and cyclohexyl esters 21 to respectively afford esters 22 and 23. Demethylationcyclization of 22 with aluminium chloride (AlCl 3 ) provided cyclic ester 24.…”

“…As a result, esterification of these two compounds gave lower yields of the ester products than those of the 2 0 ,2 0 -dimethyl analogues. 1) Naphthoquinone alcohols 32 and 33 should therefore be freshly prepared from rhinacanthones 30 and 31, respectively. Similarly, the orientation of the naphthoquinone ester products appeared folded due to the same resulting effects of rigidity and strain.…”

“…Twelve new synthetic naphthoquinone esters with 2 0 -cyclopentyl (7-12) and 2 0 -cyclohexyl (13-18) substituents were evaluated by the MTT colorimetric method 12) for their cytotoxicity against human cancer cell lines KB (human epidermoid carcinoma), HeLa (human cervical carcinoma), and HepG 2 (human hepatocellular carcinoma) (Table 1), and their activities were compared to previous naphthoquinone esters 1) with the 2 0 ,2 0 -dimethyl substituent (Table 2). was less potent than 2 0 ,2 0 -dimethyl one (6d) (IC 50 ¼ 1:59 AE 0:37 mM).…”

“…With respect to the naphthoquinone benzoate esters (7-9 and 13-15), the OH and OMe groups on the benzoate part of 2 0 -cyclopentyl naphthoquinone esters 8 and 9 conferred less activity against all three tested cancer cell lines than the one with no C-1 substitution (7) which corresponds to the analogues of the 2 0 ,2 0 -dimethyl naphthoquinone esters in our previous work. 1) In contrast, an OH group Esters 7,9,10,12,13,15,16,and 18.…”