Differential Proliferation Effect of the Newly Synthesized Valine, Tyrosine and Tryptophan–Naphthoquinones in Immortal and Tumorigenic Cervical Cell Lines

Abstract

We previously showed that microwave assisted synthesis is the best method for the synthesis of naphthoquinone amino acid and chloride-naphthoquinone amino acid derivatives by a complete evaluation of reaction conditions such as stoichiometry, bases, and pH influence. Following the same strategy, we synthesized chloride and non-chloride tyrosine, valine, and tryptophan-naphthoquinones achieving 85–95%, 80–92%, and 91–95% yields, respectively. The cyclic voltammetry profiles showed that both series of naphthoquinone amino acid derivatives mainly display one redox reaction process. Overall, chloride naphthoquinone amino acid derivatives exhibited redox potential values (E1/2) more positive than non-chloride compounds. The six newly synthesized compounds were tested in HPV positive and negative as well as in immortal and tumorigenic cell lines to observe the effects in different cellular context simulating precancerous and cancerous status. A dose-response was achieved to determine the IC50 of six newly synthesized compounds in SiHa (Tumorigenic and HPV16 positive), CaLo (Tumorigenic and HPV18 positive), C33-A (Tumorigenic and HPV negative) and HaCaT (Keratinocytes immortal HPV negative) cell lines. Non-chloride tryptophan-naphthoquinone (3c) and chloride tyrosine-naphthoquine (4a) effects were more potent in tumorigenic SiHa, CaLo, and C33-A cells with respect to non-tumorigenic HaCaT cells. Interestingly, there seems to be a differential effect in non-chloride and chloride naphthoquinone amino acid derivatives in tumorigenic versus non tumorigenic cells. Considering all naphthoquinone amino acid derivatives that our group synthesized, it seems that hydrophobic and aromatic amino acids have the greatest effect on cell proliferation inhibition. These results show promising compounds for cervical cancer treatment.

The Relevance and Insights on 1,4-Naphthoquinones as Antimicrobial and Antitumoral Molecules: A Systematic Review

“…Some PANs have been used as starting materials to prepare novel 1,4-naphthoquinone sulfonamide and sulfonate ester derivatives in good yield, as shown in Figure 5 [42]. Rivera et al, 2019, and Araujo et al, 2020, described the modification by Michael 1,4-addition, introducing several amino acids: among them are glycine, alanine, methionine, phenylalanine, asparagine, tyrosine, valine, and tryptophan in good yield (79-95%) (Figure 6) [43,44]. Some PANs have been used as starting materials to prepare novel 1,4-naphthoquinone sulfonamide and sulfonate ester derivatives in good yield, as shown in Figure 5 [42].…”

“…Lawsone Mannich bases are 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone compounds with important biological activities such as antiparasitic, antibacterial, anticancer, and antiviral, which have a particular interest in medicinal chemistry because the Mannich reaction forms a C-C bond with nitrogencontaining derivatives. This section presents molecules with promissory activity, as shown in Table 1 [31,[42][43][44][45][90][91][92]. showed MICs of 49.7 µ g mL −1 against S. aureus and 24.7 µ g mL −1 against E. coli by 63*.…”

Research status of indole-modified natural products

“…Further studies have shown that hydrophobic and aromatic amino acids have better inhibitory effects on cell proliferation. 190…”

“…Further studies have shown that hydrophobic and aromatic amino acids have better inhibitory effects on cell proliferation. 190 Shikonin is a natural product of 1,4-naphthoquinones, derived from the roots of Lithospermum species and has antitumor 191 and anti-viral activities. 192 Researchers designed and synthesized a series of shikonin derivatives, and evaluated the antitumor activity and antiviral activity of these derivatives.…”

Synthesis and Antimicrobial Evaluation of Amino Acid Naphthoquinone Derivatives as Potential Antibacterial Agents

“…An important natural compound found in plants is naphthoquinones (NQ), where 1,4-carbonyl position and hydroxyl groups in the naphthalene ring is frequent. NQ are privileged in design and drug discovery due to their structural properties and biological actions such as antibacterial [7,8], antifungal [9,10], anticancer [11][12][13], antimalarial [14], and antiviral [15]. In most cases, the biological action is related to redox and acid properties, which can be modulated by adding different atoms or groups to NQ [16].…”