Hybrid Molecules Containing Naphthoquinone and Quinolinedione Scaffolds as Antineoplastic Agents

Abstract

In recent decades, molecular hybridization has proven to be an efficient tool for obtaining new synthetic molecules to treat different diseases. Based on the core idea of covalently combining at least two pharmacophore fragments present in different drugs and/or bioactive molecules, the new hybrids have shown advantages when compared with the compounds of origin. Hybridization could be successfully applied to anticancer drug discovery, where efforts are underway to develop novel therapeutics which are safer and more effective than those currently in use. Molecules presenting naphthoquinone moieties are involved in redox processes and in other molecular mechanisms affecting cancer cells. Naphthoquinones have been shown to inhibit cancer cell growth and are considered privileged structures and useful templates in the design of hybrids. The present work aims at summarizing the current knowledge on antitumor hybrids built using 1,4- and 1,2-naphthoquinone (present in natural compounds as lawsone, napabucasin, plumbagin, lapachol, α-lapachone, and β -lapachone), and the related quinolone- and isoquinolinedione scaffolds reported in the literature up to 2021. In detail, the design and synthetic approaches adopted to produce the reported compounds are highlighted, the structural fragments considered in hybridization and their biological activities are described, and the structure-activity relationships and the computational analyses applied are underlined.

Keywords: anticancer; cytotoxicity; drug design; hybrid molecules; isoquinolinediones; medicinal chemistry; multitarget compounds; naphthoquinones; organic synthesis; quinolinequinones.

Figure 1

Molecular structures of naphthoquinones and the most common quinolinediones, and of vitamin K2 and K3.

Figure 2

Redox reactivity of naphthoquinones, here shown for 1,4-NQ with the benzoquinone and hydroquinone units depicted in blue, and the main biological targets involved in this chemical reactivity.

Figure 3

1,4-Naphthoquinone-urazole hybrids as reported by Saluja et al. [26] and arylaminonaphtoquinone hybrids as reported by Gholampour et al. [28].

Figure 4

1,4-Naphtoquinone hybrids with aminoantipyridine as reported by Rani et al. [29], with chloroquinoline by Fiorot et al. [30] and with chalcone by Nguyen et al. [31].

Figure 5

1,4-Naphtoquinone-polyamine hybrids as reported by Bolognesi et al. [32].

Figure 6

1,4-Naphthoquinone hybrids with 1,2,3-triazole as reported by Gholapour et al. [33] and with N-sulfonyl 1,2,3,-triazole by Valença et al. [34].

Figure 7

1,4-Naphthoquinone hybrids as reported by Prasad et al. [35] and by da Cruz et al. [36].

Figure 8

1,4-Naphthoquinone-carbohydrate hybrids as reported by Chakraborty et al. [38].

Figure 9

1,4-Naphthoquinone-diaminodiphenyl sulfone hybrids as reported by Alimohammadi et al. [39].

Figure 10

Shikonin-lipoic acid hybrid as reported by Lin et al. [41].

Figure 11

1,4-Naphthoquinone hybrids with 4-aza-podophyllotoxin as reported by Yang et al. [42] and with diazeniumdiolate scaffold by Bao et al. [43].

Figure 12

Naphthofurandione–phosphonate hybrids as reported by Janecka and coworkers [44,45].

Figure 13

1,4-Naphthoquinone hybrids with imino- and amino-urane scaffold as reported by Zhou et al. [46].

Figure 14

1,4-Naphthoquine-thiazole-paracyclophane hybrids as reported by Aly et al. [47].

Figure 15

Steroid-anthraquinone hybrids as reported by De Riccardis et al. [48].

Figure 16

Sugar–oxasteroid–quinone hybrids as reported as reported by Kaliappan and coworkers [49,50].

Figure 17

The 1,2-naphthoquinone-2-acetyl furane hybrid as reported by Löcken et al. [52].

Figure 18

1,2-Naphthoquinone hybrids with 2-functionalized furan as reported by Bian et al. [53] and with 2-amino oxazole by Li et al. [54], and by Yu et al. [55].

Figure 19

1,2-Naphthoquinone-substituted 1,2,3-triazole hybrids as reported by da Silva Júnior, et al. [56], by Wu et al. [57] and by Chipoline et al. [58].

Figure 20

1,2 Naphthoquinone hybrids with coumarin-dimethosxyaryl scaffolds as reported by Martin-Rodriguez et al. [59] and with spirooxindole-tetrazolopyrimidine by Wu et al. [60].

Figure 21

1,2-Naphthoquinone hybrids containing the 2-substituted pyrimidine scaffold as reported by Zhou et al. [61] and the 1,3,4-thiadiazolo [3,2-a]pyrimidine scaffold by Wu and Zhang [62].

Figure 22

β-Lapachone-chalcogen (Se or S) hybrids as reported as reported by Vieira et al. [63].

Figure 23

Lapachone or nor-lapachone–substituted 1,2,3-triazole hybrids as reported by Bahia et al. [64], and by Costa et al. [65].

Figure 24

1,4- and 1,2 -Naphtoquinone hybrids as reported by da Silva Júnior et al. [66].

Figure 25

Lapachone hybrids with 1,2,3-triazole or chalchone, or nitro group units as reported by Jardim et al. [67].

Figure 26

Lapachone-1,2,3-triazole with selenium functionalization hybrids as reported by da Cruz et al. [68].

Figure 27

Molecular structures and cytotoxic data of the most active Se- containing compounds as reported by da Cruz et al. [68].

Figure 28

1,4- and 1,2-Naphthoquinone–organoselenium hybrids as reported by Jardim et al. [69].

Figure 29

Nor-lapachone-BODYPY fluorophore hybrids as reported by Gontijo et al. [70].

Figure 30

Quinolinedionefurandione–phosphonate hybrids as reported by Modranka et al. [71].

Figure 31

1,4-Naphthoquinone or quinoline 5,8-dione hybrids with diosgenin as reported by Li et al. [72].

Figure 32

1,4-Naphthoquinone, quinoline 5,8-dione and isoquinoline-5,8-dione scaffolds in hybrids with betulin as reported by Kadela-Tomanek et al. [73,74,75].

Figure 33

1,4-Naphthoquine and quinolone-5,8-dione scaffolds in alkylamino-trimethoxyl hybrids as reported by Defant and Mancini [76].

Figure 34

5,8-Isoquinolinedione-carbohydrate hybrids as reported by da Silva et al. [77].

Figure 35

1,4-Naphthoquinone and isoquinolinedione-4-oxoquinoline hybrids as reported by Mello et al. [78].

Figure 36

Relative abundance of scaffolds used in the molecular hybridization: (a) naphthoquinone types, and (b) other fragments, as reported in the papers herein reviewed.