Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy

Abstract

Despite the recent advances in the field of chemically synthetized pharmaceutical agents, nature remains the main supplier of bioactive molecules. The research of natural products is a valuable approach for the discovery and development of novel biologically active compounds possessing unique structures and mechanisms of action. Although their use belongs to the traditional treatment regimes, plant-derived compounds still cover a large portion of the current-day pharmaceutical agents. Their medical importance is well recognized in the field of oncology, especially as an alternative to the limitations of conventional chemotherapy (severe side effects and inefficacy due to the occurrence of multi-drug resistance). This review offers a comprehensive perspective of the first blockbuster chemotherapeutic agents of natural origin's (e.g. taxol, vincristine, doxorubicin) mechanism of action using 3D representation. In addition is portrayed the step-by-step evolution from preclinical to clinical evaluation of the most recently studied natural compounds with potent antitumor activity (e.g. resveratrol, curcumin, betulinic acid, etc.) in terms of anticancer mechanisms of action and the possible indications as chemotherapeutic or chemopreventive agents and sensitizers. Finally, this review describes several efficient platforms for the encapsulation and targeted delivery of natural compounds in cancer treatment.

Keywords: bioactive compounds; chemoprevention; doxorubicin, paclitaxel, vincristine, resveratrol, curcumin, rutin, betulinic acid, antitumoral effect.

Figure 1

Chemical structures of (1) doxorubicin, (2) daunorubicin, (3) epirubicin, (4) idarubicin and (5) bleomycin.

Figure 2

(a) Crystallographic 3D structure of doxorubicin (gold) in complex with DNA (PDB ID: 151D), d(CGATCG) and (b) the anthracycline structure is strongly bound to DNA base pairs through multiple hydrogen bonds (HBs) depicted as green dotted lines; DNA-ligand representation was achieved using Biovia Discovery Studio 4.1 (Dassault Systems).

Figure 3

(a) Chemical structures of (1) paclitaxel, (2) docetaxel, and (3) cabazitaxel, major structural differences are highlighted in green while alkylation/acylation of OH groups is highlighted in red; (b) 3D structure of stabilized microtubule chain A (blue) (PDB ID: 5SYF) in complex with taxol (gold) and (c) important HBs (green dotted lines) formed by the taxane structure within the β-tubulin binding site. Protein-ligand representation was achieved using Biovia Discovery Studio 4.1 (Dassault Systems).

Figure 4

Chemical structures of (1) vincristine, (2) vinblastine, (3) vindesine, (4) vinorelbine, (5) vinflunine, (6) podophyllotoxin, (7) etoposide and (8) teniposide.

Figure 5

DNA-topoisomerase IIα-etoposide complex (PDB ID: 5GWK); HB (green dotted lines) formed by etoposide (yellow sticks) with interacting amino acids (blue sticks) and nucleotides (orange sticks).

Figure 6

Chemical structures of (1) resveratrol, (2) curcumin, (3) EGCG, (4) quercetin, (5) rutin, (6) betulinic acid and (7) artesunate.

Figure 7

Curcumin (light green) in in complex with DYRK2 (PDB ID: 5ZTN); the compound interacts with the surrounding aminoacid residues through multiple HBs (green dotted lines) and several hydrophobic interactions (purple dotted lines). Protein-ligand representation was achieved using Biovia Discovery Studio 4.1 (Dassault Systems).

Figure 8

Apigenin (light green) in in complex with TNK2 (PDB ID: 4HKK); the flavone interacts with the surrounding amino acid residues through multiple HBs (green dotted lines) and several hydrophobic interactions (purple dotted lines). Protein-ligand representation was achieved using Biovia Discovery Studio 4.1 (Dassault Systems).