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Journal of Molecular and Clinical Medicine   2019, Vol. 2 Issue (2): 35-40    DOI: 10.31083/j.jmcm.2019.02.7181
Original Research Previous articles | Next articles
Naphthol-derived Betti bases as potential SLC6A14 blockers
Adrián Puerta1, Alexis R. Galán1, Roderick Abdilla2, Kaylie Demanuele2, Miguel X. Fernandes1, Giovanna Bosica2, José M. Padrón1, *()
1 BioLab, Instituto Universitario de Bio-Orgánica Antonio González (IUBO AG), Universidad de La Laguna, PO BOX 456, 38200 La Laguna, Spain
2 Department of Chemistry, University of Malta, Msida, MSD 2080, Malta
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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 (GI50) 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.

Key words:  Anti-proliferative activity      Betti bases      breast cancer      multicomponent reactions      solute carrier protein      SLC6A14(ATB0,+)     
Published:  20 April 2019     
*Corresponding Author(s):  José M. Padrón     E-mail:  jmpadron@ull.es

Cite this article: 

Adrián Puerta, Alexis R. Galán, Roderick Abdilla, Kaylie Demanuele, Miguel X. Fernandes, Giovanna Bosica, José M. Padrón. Naphthol-derived Betti bases as potential SLC6A14 blockers. Journal of Molecular and Clinical Medicine , 2019, 2(2): 35-40.

URL: 

https://jmcm.imrpress.com/EN/10.31083/j.jmcm.2019.02.7181     OR     https://jmcm.imrpress.com/EN/Y2019/V2/I2/35

Figure 1.  General structure of scaffolds obtained by MCRs, with indication of the anti-proliferative activity (GI50) of the resulting leads.

Figure 2.  General procedure for the synthesis of Betti bases. Reagents and conditions: (a) Montmorillonite K30, neat, 60 oC or r.t. See Table 1 for amine and R definitions.

Table 1  Anti-proliferative activity (GI50) against human solid tumor cell lines of the Betti bases of 2-naphthola
Cell line
Compound Amine R A549 HBL-100 HeLa SW1573 T-47D WiDr
14a Pyrrolidine Ph > 100 > 100 > 100 > 100 > 100 > 100
14b p-MePh 14 ± 0.9 41 ± 0.6 16 ± 4.7 15 ± 0.8 26 ± 5.2 32 ± 1.5
14c p-NO2Ph 92 ± 1.0 > 100 15 ± 1.9 63 ± 24 13 ± 3.1 > 100
14d p-CNPh > 100 > 100 > 100 42 ± 2.0 55 ± 9.1 > 100
14e o-MeOPh 17 ± 0.7 28 ± 5.2 15 ± 3.0 20 ± 3.1 27 ± 3.9 28 ± 2.1
14f m-MeOPh 26 ± 8.1 56 ± 11 22 ± 1.6 29 ± 3.9 29 ± 0.9 36 ± 5.9
14g p-MeOPh 30 ± 6.0 27 ± 5.4 27 ± 2.5 23 ± 4.5 32 ± 4.0 35 ± 5.6
14h p-FPh 21 ± 6.3 48 ± 11 23 ± 5.8 25 ± 4.7 29 ± 1.4 55 ± 6.3
14i p-ClPh 12 ± 2.4 25 ± 2.4 27 ± 2.6 14 ± 0.3 19 ± 2.1 33 ± 2.9
14j p-BrPh 7.9 ± 0.2 9.4 ± 3.2 8.3 ± 1.4 14 ± 2.2 16 ± 5.5 37 ± 12
14k p-3,4-diClPh 12 ± 3.9 22 ± 12 8.4 ± 2.5 22 ± 7.4 9.8 ± 2.3 36 ± 8.8
14l 4-Pyridyl 40 ± 3.6 62 ± 2.1 37 ± 5.2 18 ± 5.9 64 ± 15 68 ± 16
14m Piperidine p-MePh 30 ± 8.9 53 ± 4.2 23 ± 3.0 31 ± 7.5 25 ± 3.1 44 ± 4.2
14n p-NO2Ph 66 ± 26 82 ± 25 8.1 ± 1.2 66 ± 10 13 ± 3.3 > 100
14o p-CNPh 79 ± 30 76 ± 27 11 ± 0.7 29 ± 13 8.5 ± 0.7 93 ± 0.7
14p Morpholine p-MePh 28 ± 4.2 24 ± 2.4 18 ± 1.8 18 ± 2.6 28 ± 0.7 31 ± 6.6
14q p-NO2Ph 22 ± 0.5 31 ± 9.1 13 ± 1.5 34 ± 11 27 ± 3.8 51 ± 7.4
14r p-CNPh 28 ± 3.9 33 ± 1.7 18 ± 1.7 17 ± 7.9 27 ± 4.8 31 ± 6.4
14s BnNH2 Ph 55 ± 2.5 30 ± 4.8 16 ± 5.4 25 ± 2.5 27 ± 3.5 45 ± 7.0
14t BnNH2 p-CNPh 12 ± 3.3 5.0 ± 0.1 4.1 ± 0.6 6.3 ± 1.2 8.4 ± 1.2 30 ± 6.3
14u n-BuNH2 Ph > 100 > 100 > 100 > 100 > 100 > 100
14v i-PentNH2 Ph 19 ± 3.1 19 ± 2.8 13 ± 1.4 22 ± 3.9 20 ± 2.7 25 ± 4.7
14w c-PentNH2 Ph 18 ± 3.9 24 ± 0.6 18 ± 5.5 15 ± 3.6 25 ± 0.2 33 ± 7.5
CDDP 4.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.5 2.7 ± 0.4 17 ± 3.3 23 ± 4.3
Table 2  Anti-proliferative activity (GI50) of selected Betti bases against breast cancer cellsa
Cell line (subtype)
Compound HBL-100
(TNBC)
MDA-MB-453
(HER2+)
MCF-7
(ER+)
T-47D
(ER+)
14c > 100 94 ± 11 63 ± 11 13 ± 3.1
14d > 100 42 ± 7.0 53 ± 12 55 ± 9.1
14n 82 ± 25 96 ± 9.9 > 100 13 ± 3.3
14o 76 ± 27 59 ± 9.1 56 ± 10 8.5 ± 0.7
α-MT > 100 > 100 > 100 > 100
Table 3  Docking scores of α-MT and selected Betti bases
Docking interaction energy (kcal mol-1)
Compound R enantiomer S enantiomer
14c -7.1 -6.3
14d -6.3 -6.3
14n -5.9 -6.3
14o -6.3 -6.2
α-MT -6.8 -6.8
Figure 3.  Dock superimposed pose of α-MT (pink) with 14c (blue) and 14d (yellow).

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