Synthesis and Evaluation as Antitumor Agents of 1,4‐Naphthohydroquinone Derivatives Conjugated with Amino Acids and Purines

Abstract

We report on the synthesis of two series of 1,4-naphthohydroquinone derivatives conjugated with amino acids (Gly, Ala, Phe, and Glu) and with substituted purines linked by an aliphatic chain. The compounds were obtained through Diels-Alder cycloaddition between myrcene and 1,4-benzoquinone and evaluated in vitro for their cytotoxicity (GI50 ) against cultured human cancer cells of A-549 lung carcinoma, HT-29 colon adenocarcinoma, and MCF-7 breast carcinoma. The GI50 values found for some hydroquinone-amino acid and hydroquinone-purine hybrids against MCF-7 are in an activity range comparable to that of the reference drug doxorubicin.

Bioactive Prenyl- and Terpenyl-Quinones/Hydroquinones of Marine Origin †

“…Considering the potentiality of dual targeting in drug design and development, several quinone/HQ hybrids with nitrogen heterocycles [ 184 , 185 ] and with other biogenic compounds as aminoacids, purines [ 186 ] and cyclolignans [ 187 ] ( Figure 52 ), were obtained and bioassayed. The latter were named as lignoditerpenylhydroquinones, and they showed a very interesting and selective cytotoxicity against the osteosarcoma cell line MG-63, which is a very aggressive cancer, opening a new perspective for its treatment [ 187 ].…”

New 1H-Benzo[f]indazole-4,9-diones Conjugated with C-Protected Amino Acids and Other Derivatives: Synthesis and in Vitro Antiproliferative Evaluation

“…Molecules 2015, 20, page-page 4 carboxylic group was then enhanced through the in situ formation of the mixed anhydride with ethyl chloroformate followed by the addition of the corresponding methyl ester of glycine, L-alanine, L-phenylalanine and L-glutamic acid [25]. In all of these synthesized compounds, the L-configuration must be retained in the amino acid unit.…”

“…We have recently reported the synthesis of unsubstituted and N-substituted 3-methyl-7-(4-methylpent-3-enyl)-1H-benzo[f ]indazole-4,9-diones 2 from the reaction of 2-acetyl-6-(4-methylpent-3-enyl)-1,4-naphthoquinone 1 with hydrazine or substituted hydrazines [23]. The objective of this work was to continue previous research on the design and synthesis of new potentially cytotoxic 1,4-naphthoquinone compounds [24,25] while taking into account the enhanced cytotoxic effect that has been observed in drugs or compounds conjugated with amino acids [26,27]. Therefore, we prepared twenty one new 1H-benzo[f ]indazole-4,9-dione compounds conjugated with glycine and the L-type amino acids alanine, phenylalanine, and glutamic acid 6a-l, as well as the epoxides 3a-c, aldehydes 4a-c and carboxylic acids 5a-c, by chemically modifying the prenyl 7-(4-methylpent-3-enyl) substituent of 2.…”

New Antineoplastic Naphthohydroquinones Attached to Labdane and Rearranged Diterpene Skeletons

“…We have prepared a large number of derivatives with variations in sizes and functionalities of both the quinone and the terpenoid moieties. Very interesting antineoplastic compounds were obtained from β-myrcene [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ] and myrceocommunic acid [ 11 , 12 , 13 , 14 ], being the DTQs/DTHQs slightly more potent than the MTQs/MTHQs. About the quinone size, 1,4-naphthoquinone (NQ) and 1,4-anthracenequinone (AQ) analogues were more potent than the corresponding benzoquinones (BQs) and 9,10-AQs, the common moiety in clinically used anticancer drugs, without significant differences between the quinone functions and the corresponding acetylated hydroquinones.…”

“…In our previous research, many MTQs/MTHQs have been obtained by transformation of the side chain derived from the monoterpenoid [ 5 , 6 , 9 , 10 ], however only a few examples dealt with modifications of the diterpenoid core, always keeping the labdane type decalin [ 11 , 12 ]. Now, we describe further chemical transformations performed at this decalin moiety in the DTHQ series, either at the A or B decalin rings, including isomerizations, decarboxylations or rearrangements, leading to derivatives with modified diterpenoid skeletons, which have been evaluated against four tumor cell lines, representative of common and multi-drug resistant cancer types affecting lung, colon, breast and skin, to analyze the influence of those modifications on their cytotoxicity.…”