Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine's Tool Box

Abstract

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds. Nevertheless, as for any other promising anticancer drugs, heterocyclic compounds do not come without shortcomings. In this review, we provide for a concise overview of heterocyclic active compounds and families and their main applications in medicine. We shall focus on those suitable for cancer therapy while simultaneously addressing main biochemical modes of action, biological targets, structure-activity relationships as well as intrinsic limitation issues in the use of these compounds. Finally, considering the advent of nanotechnology for effective selective targeting of drugs, we shall discuss fundamental aspects and considerations on nanovectorization of such compounds that may improve pharmacokinetic/pharmacodynamic properties of heterocycles.

Keywords: cancer therapy; drug delivery; heterocyclic compounds; nanomedicine; oxygen and nitrogen-based heterocycles.

Figure 1

Heterocycle molecule drugs present in the US top five prescription drugs and respective retail sales in 2014 (in billions of U.S. $) [15].

Figure 2

Chemical structure representation of indole basic core structure and of reported/FDA approved examples of indole like compounds as tubulin inhibitors [29].

Figure 3

Chemical structure representation of a novel indole-bearing combretastatin analogues as tubulin polymerization inhibitors with antiproliferative activities against tumor cell lines THP1 and MCF7 [29].

Figure 4

Chemical structure representation of a novel indole compound SK228 with reported antiproliferative activities through the induction of reactive oxygen species, activation of programed cell death processes and the disruption FAK/Paxillin pathway [30].

Figure 5

Chemical structure representation of a promising imidazole derivative with proven antiproliferative activity in A549 epithelial cancer cells, by affecting proliferation, migration, anchorage independent growth, and by inducing cycle arrest in the G2/M phase plus the activation of apoptosis [32].

Figure 6

Chemical structure representation of N-(1-(2, 6-difluorob- benzyl)-piperidine-4-yl)-4-phenoxybenzamide complex with proven antiproliferative activity in HepG2 cells, through regulation of AMPK phosphorylation and by induction of cell cycle arrest p53/p21-dependent manner [33].

Figure 7

Chemical structure representation of synthetized benzimidazole hybrid heterocycles with superior selectivity for leukemia cell lines (11) and for non-small cell lung cancer cell lines (12) [35,36].

Figure 8

Chemical structure representation of synthetized triazolo[1,3,4]thiadiazole derivative, 6-(4-chlorophenyl)-3-(pyridin-4-yl)-[1,2,4]triazolo[3,4-b], with proven antiproliferative activity, with superior selectivity for gastric cancer cell lines [37].

Figure 9

Chemical structure representation of FDA approved oxygen-based heterocycles, Cabazitaxel (14), with an oxetane ring, and Eribulin (15) with tetrahydrofuran and tetrahydropyran rings [39,40].

Figure 10

Chemical structure representation of synthetized benzosuberone derivatives bearing coumarin moieties with promising antiproliferative activity against A549, HeLa, MCF7 and MDA-MB-231 cell lines [41].

Figure 11

Chemical structure representation of flavanone core scaffold (18) and flavanone derivative, furfuraldehyde (19) with a reasonable cytotoxic activity against HT29, MCF7 and A498 cancer cell lines [47].

Figure 12

Chemical structure representation of benzofuran core scaffold (20) and benzofuran derivative, N-(40-hydroxy)phenylamide (21) with proven anticancer activity against HCT15, ACHN, NUGC-3, MM23, PC-3 and NCI-H23 cell lines through the inhibition of NF-κB activity [49].

Figure 13

Chemical structure representation of 2,3,4-trisubstituted oxazolidines core scaffold (22) and oxazolidine derivative, (S)-tert-butyl 2,2-dimethyl-4-(1-(4-nitrophenyl)vinyl)oxazolidine-3-carboxylate (23) with proven anticancer activity against HL60, JURKAT, MDA-MB-231 and LNCaP [51].

Figure 14

Chemical structure representation of N-(3- cyano-5,6-dihydro-4H-cyclopenta (b) thiophene active derivatives, N-(3-Cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2-(4-(N-(pyrimidin-2yl) sulfamoyl,sodiumsalt) phenylamino) acetamide (24) and 4-(5,6-dihydro-7H-cyclopenta (4:5) thieno (2,3-d)-1,2,3-triazin-4-ylamino)phenol (25) with particular antiproliferative activity for MCF7 through the inhibition of ATP recognition binding sites of tyrosine kinase receptors [58].

Figure 15

Chemical structure representation of synthetized thiophene derivatives Complexes (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-1-enylamino)-N-(thiazol-2-yl)benzenesulfonamide (26), (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-1-enylamino)-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (27), (Z)-4-(3-oxo-3-(thiophen-2-yl)prop-1-enylamino)-N-(pyrimidin-2-yl)benzenesulfonamide (28) and (Z)-3-(4-methoxybenzo[d]thiazol-2-ylamino)-1-(thiophen-2-yl)prop-2-en-1-one (29) with promising antiproliferative activity against MCF7 cell line, [59].

Figure 16

Chemical structure representation of compound (E)-N-(4-(2-(2-(4-(bis(2-chloroethyl)amino)benzylidene)hydrazinyl)thiazol-4-yl)phenyl)methanesulfonamide (8) with proven anticancer activity against HCT116 and MCF7 cell lines [64].

Figure 17

Chemical structure representation of synthetized benzothiophene acrylonitrile derivatives, ([Z-3-(benzo[b]thiophen-2-yl)-2-(3,4-dimethoxyphenyl)acrylonitrile] (31), [Z-3-(benzo[b]thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile] (32) and [E-3-(benzo[b]thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile]) (33) with promising antiproliferative activity [65].

Figure 18

Impact of heterocyclic FDA approved anti-tumor drugs during the calendar years of 2010–2015 (A) and their respective discrimination by class and frequency (B) [22].

Figure 19

Benzo[d]pyrrolo[2,1-b]thiazole with bis(i-propylcarbamates) derivatives with proven cytotoxic activity against lymphoblastic leukemia CCRF-CEM and human breast carcinoma MX-1 xenografts [73].

Figure 20

Number of heterocyclic compounds nanoformulations currently in clinical trial (red bars) and FDA approved (blue bars) for cancer therapy. Lipid based carriers nanoformulations include liposomes; Drug conjugates include antibody-drug conjugates and polymer-drug conjugates; Polymeric carriers include nanoparticle albumin bound technology, polymeric micelles and polymeric nanoparticles [77,89].