Synthesis of Naphthoic Acids as Potential Anticancer Agents

Abstract

As part of ongoing research to investigate structural requirements for lactate dehydrogenase inhibition by highly substituted naphthoic acids, nine new aryl-substituted dihydroxynaphthoic acids were synthesized from three known precursors. Described here are efficient preparations of the 1-naphthoic acid target compounds by using Suzuki coupling reactions, formylations, oxidations, and demethylations. Lactate dehydrogenase inhibition studies conducted with five of the compounds revealed values of the inhibitory constant K _i in the low micromolar range.

Key words

naphthoic acids - Suzuki coupling - naphthaldehydes - formylation - oxidation - medicinal chemistry

• References and Notes

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• 37 Naphthalenes 12a–e; General Procedure Bromide 11 was combined with the appropriate arylboronic acid in EtOH. K₃PO₄, TBAB, PdCl₂, and H₂O were added, and the mixture was stirred at r.t. or heated until the starting material was completely consumed (TLC). The mixture was filtered through a small pad of silica gel, eluting with EtOAc, and the filtrate was washed with 1 M aq NaOH. The organic phase was separated, washed with sat. aq NaCl, then dried (MgSO₄) and filtered. The solvent was evaporated to give a crude product, which was purified chromatographically. 2,3-dimethoxy-7-methyl-6-phenyl-1-propylnaphthalene (12a) White crystals; yield: 60%; mp 111–113 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.81 (s, 1 H, NaH⁸), 7.63 (s, 1 H, NaH⁵), 7.45 (m, 5 H, ArH², ArH³, ArH⁴, ArH⁵, ArH⁶), 7.07 (s, 1 H, NaH⁴), 3.98 (s, 3 H, OCH₃), 3.94 (s, 3 H, OCH₃), 3.12 (t, J = 7.9 Hz, 2 H, NaCH₂), 2.46 (s, 3 H, NaCH₃), 1.78 (sextet, J = 7.5 Hz, 2 H, C-CH₂-C), 1.15 (t, J = 7.3 Hz, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 152.1 (NaC³), 147.1 (NaC²), 142.2, 140.0, 131.6, 130.2, 130.1, 129.5 (ArC³H, ArC⁵H), 128.2 (ArC²H, ArC⁶H), 128.0, 127.6, 126.9, 124.7 (NaC¹), 105.3 (NaC⁴H), 61.2 (OCH₃), 55.6 (OCH₃), 27.9 (NaCH₂), 24.2 (CH₂), 21.5 (NaCH₃), 14.8 (CH₃). HRMS (EI): m/z [M + H]⁺ calcd for C₂₂H₂₅O₂: 321.1855; found: 321.1849.