Cancer Cells Show Higher Sensitivity to Melatonin-Tamoxifen Drug Conjugates than to Combination of Melatonin and Tamoxifen

Abstract

Drug conjugates of tamoxifen and melatonin linked through the amide side chain of melatonin (4a,4b) were reported as promising agents for future treatment of breast cancer, possibly reversing the adverse effects of tamoxifen. Here, we report the synthesis and pharmacological evaluation of a novel series of anticancer drug conjugates linking melatonin with tamoxifen through polymethylene spacers through the ether oxygen of melatonin (16a-c, 19a-c, 21) and compare them to the previously reported amide-linked analogues 4a and 4b. All hybrid ligands are antagonists of estrogen receptor alpha and agonists of the melatonin MT₁ receptor with variable potencies. Several drug conjugates including the (CH₂)₄-linked analogues 4a and 16a and the (CH₂)₆-linked compound 16c showed higher potency to inhibit cell viability than the combination of melatonin and tamoxifen on at least one cancer cell line including MCF-7, MDA-MB-231, and HT-1080.

Figure 1

Structures of melatonin, tamoxifen, 4-OH-tamoxifen and of selected drug conjugates incorporating the latter drugs.

Scheme 1. Synthesis of drug conjugate 11

Reagents and conditions: (i) 1. NaH, DMF, 2. Br(CH₂)₆CO₂Et; (ii) 1. 2M LiOH, THF, 2. 1M HCl; (iii) 1. EDCI HCl, DIPEA, HOBt, CH₂Cl₂; 2. N-deacetylmelatonin.

Scheme 2. Synthesis of drug conjugates 16a–c

Reagents and conditions: (i) 1. NaH, DMF, 2. Br(CH₂)_nCO₂R; (ii) 1. 2M LiOH, THF, 2. 1M HCl; (iii) Cs₂CO₃, KI, MeCN, BocNH(CH₂)₃Br; (iv) Me₃SiBr, MeCN; (v) 1. EDCI HCl, DIPEA, HOBt, CH₂Cl₂.

Scheme 3. Synthesis of drug conjugates 19a–c

Reagents and conditions: (i) 1. Cs₂CO₃, KI, MeCN, Br(CH₂)_nCO₂R; (ii) 1. 2M LiOH, THF, 2. 1M HCl; (iii) 1. EDCI HCl, DIPEA, HOBt, CH₂Cl₂, 2. nortamoxifen.

Scheme 4. Synthesis of Drug Conjugate 21

Reagents and conditions: (i) Cs₂CO₃, CH₃CN, 1,2-bis(2-iodoethoxy) ethane, rt, 24 h; (ii) O-demethylmelatonin, Cs₂CO₃, CH₃CN, 24 h, rt.