Antitumor studies of different diterpenoids and derivatives from Plectranthus spp.

Abstract

Cancer is a multi-target and multifactorial disease that is usually treated using surgery, chemotherapy, radiation therapy, and/or biological drugs, either alone, in combination or alternately. However, the use of these therapies leads not only to the appearance of adverse effects but also to drug resistance. Among the possible types of cancer, Glioblastoma (GB), is the most common brain tumour and is characterized by its invasiveness and, for becoming resistant to the most common chemotherapy treatment performed with Temozolomide (TMZ). Due to these circumstances, these patients have a life expectancy of one and a half years after diagnosis and 5% survival in 5 years. That is the reason why it is necessary to find new treatments to overcome this problem with namely new natural sources approaches. In this project, it is given a broad vision of the functionality of natural products as sources for the development of new drugs, which includes not only the use of plants but also the use of compounds derived from or used by animals (Zoopharmacognosy) or compounds derived from other natural products. Plants produce different types of secondary metabolites, such as terpenes, which are synthesized to interact with their environment, allowing them, for example, to defend themselves from external agents. These terpenes are currently being studied as sources of new antitumor and antibacterial treatments against resistant strains. Plants of the Plectranthus genus (Lamiaceae) are known to be rich in abietane diterpenes of the royleanone type, such as 7α-acetoxy-6βhydroxyroyleanone (Roy), 6β,7β-dihydroxyroyleanone (DiRoy) and Parviflorone D (ParvD). Bioguided isolation of acetonic extract from branches of the species P. hadiensis (Forssk.) Schweinf. ex Sprenger, resulted in the obtention of six fractions. In fractions III and V, which were the most active in antioxidant and antimicrobial assays, separation was continued until Roy and DiRoy compounds were isolated and structurally characterized with techniques such as NMR. These compounds turned out to be the major ones according to the profile of the extract by HPLC-DAD. When testing these compounds in GB cell lines U87, A172, U118, U373 and H4, Roy evidenced low IC50 values in the Alamar blue assay. In addition, the use of the probe synthetic derivative BODIPY-Roy showed that the compound was able to pass to cells, since its fluorescence was increased, which seconded the significant antiproliferative effects of Roy. On the other hand, an extensive review of the phytochemistry and bioactivity of P. ecklonii Benth is presented. The ParvD isolated and characterized from acetonic extract showed a more pronounced antiGB activity and at lower doses than the TMZ (in the same cell lines mentioned above, the IC50 values for ParvD were between 13 and 175 times lower than the ones for TMZ). The mechanism involved in this effect was proven to be the intrinsic apoptosis in tumour cells. In another study, it was also evidenced that the isolated compound ParvD inhibits tyrosinase (72.7±5.6 % enzyme inhibition), collagenase (84.6±5.9 % enzyme inhibition) and, to a lesser extent, elastase (52.8±3.8 % enzyme inhibition), which makes this plant not only interesting for the treatment of GB, but also for dermal pathologies. Currently, the study of the extraction optimization of these bioactive compounds from different Plectranthus spp., the synthesis of some derivatives and their mechanism of action in vivo is being concluded to develop these terpenes as new drugs. Ultimately, an educational practice is proposed in which a bioactive derivative of the antibiotic nalidixic acid (a subproduct of the synthesis of the natural alkaloid quinine) is synthesized by mechanochemistry with greater antibiotic properties than the starting compound, with the aim of proposing, transferring, and implementing new teaching practices.