Naphthol-derived Betti bases as potential SLC6A14 blockers

Abstract

Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI 50 ) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na + -and Cl − -dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJ-hTERT.

Synthesis, Computational, and Anticancer In Vitro Investigations of Aminobenzylnaphthols Derived from 2-Naphtol, Benzaldehydes, and α-Aminoacids via the Betti Reaction

“…Since then, the Betti reaction has returned to the interest of organic chemists around the world and is now experiencing its second youth. Aminobenzylnaphthols formed in this transformation, the so-called Betti bases, are a class of molecules found in many natural and synthetic compounds with a wide range of interesting activities and applications [13]. Betti base derivatives were tested as antitumor agents [14], sodium-and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14) blockers [13], antiyeast agents inhibiting Candida albicans growth [15], antitumor and antioxidants [16], and multidrug resistance (MDR) reversal agents [17].…”

“…Compound 14j had the highest antiproliferative activity against the human breast cancer cell line A549, with GI 50 values of 7.9 µM, while the reference drug (cisplatin) had a GI 50 value of 4.9 µM. Compound 14t was found to have significant antiproliferative action, with GI 50 values in the micromolar range: HBL100 (5 µM), HeLa (4.1 µM), SW1573 (6.3 µM), and T47D (8.4 µM) (Figure 1) [13]. Furthermore, docking experiments demonstrated that Betti bases disrupt the SLC6A14 solute transporter, resulting in amino acid deprivation and suppressing the proliferation of cells by acting as tryptophan mimetics [13].…”

“…Furthermore compounds demonstrated promising cytotoxic and antiproliferative activity against the human cervical cancer cell line (HeLa), with IC50 values ranging from 4.63 to 5.54 μM [18] Puerta et al [13] synthesized a library of 23 Betti bases and tested their cytotoxic activities against human breast cancer cell lines (A549, HBL-100, T-47D), human cervical cancer cell line (HeLa), alveolar cell carcinoma (SW1573), and human colon cancer cell line (WiDr) Compound 14j had the highest antiproliferative activity against the human breast cancer cell line A549, with GI50 values of 7.9 μM, while the reference drug (cisplatin) had a GI50 value of 4.9 μM. Compound 14t was found to have significant antiproliferative action with GI50 values in the micromolar range: HBL100 (5 μM), HeLa (4.1 μM), SW1573 (6.3 μM), and T47D (8.4 μM) (Figure 1) [13]. Furthermore, docking experiments demonstrated that Betti bases disrupt the SLC6A14 solute transporter, resulting in amino acid deprivation and suppressing the proliferation of cells by acting as tryptophan mimetics [13].…”

“…Compound 14t was found to have significant antiproliferative action with GI50 values in the micromolar range: HBL100 (5 μM), HeLa (4.1 μM), SW1573 (6.3 μM), and T47D (8.4 μM) (Figure 1) [13]. Furthermore, docking experiments demonstrated that Betti bases disrupt the SLC6A14 solute transporter, resulting in amino acid deprivation and suppressing the proliferation of cells by acting as tryptophan mimetics [13]. Recently, there has been renewed interest in the use of amino acid derivatives as prodrugs.…”

“…J = 8.6 Hz, H Ar ), 7.73 (d, 2H, J = 8.7 Hz, H Ar ), 12.33 (s, 1H, OH);13 C NMR (CDCl 3 ) δ: 37.5 (CH 2 ), 52.1 (OCH 3 ), 52.6 (OCH 3 ), 55.5 (CHCO), 62.0 (CHAr 2 ), 112.5, 120.0, 121.2, 122.7, 126.7, 128.0, 128.2, 128.7, 128.8, 129.1, 130.1, 132.9, 140.2, 156.6 (C Ar ), 170.9 (CO), 173.0 (CO); elementar analysis: C 23 H 23 NO 5 (393.44 g/mol) calculated: C% 70.21, H% 5.89, N% 3.56; found: C% 70.02, H% 5.96, N% 3.61.…”