antibiotics Article Biological Profiling of Semisynthetic C19-Functionalized Ferruginol and Sugiol Analogues Miguel A. González-Cardenete 1,* , Fatima Rivas 2 , Rachel Basset 2, Marco Stadler 3, Steffen Hering 3, José M. Padrón 4 , Ramón J. Zaragozá 5 and María Auxiliadora Dea-Ayuela 6,* 1 Instituto de Tecnología Química (UPV-CSIC), Universitat Politècnica de València-Consejo Superior de Investigaciones Científicas, Avda. de los Naranjos s/n, 46022 Valencia, Spain 2 Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; [email protected] (F.R.); [email protected] (R.B.) 3 Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria; [email protected] (M.S.); [email protected] (S.H.) 4 BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna, C/Astrofísico Francisco Sanchez 2, 38200 La Laguna, Spain; [email protected] 5 Departamento de Química Orgánica, Universidad de Valencia, Dr. Moliner 50, 46100 Burjassot, Spain; [email protected] 6 Departamento de Farmacia, Facultad Ciencias de la Salud, Universidad CEU Cardenal Herrera, C/Ramón y Cajal s/n, 46115 Alfara del Patriarca, Spain * Correspondence: [email protected] (M.A.G.-C.); [email protected] (M.A.D.-A.) Abstract: The abietane-type diterpenoids are significant bioactive compounds exhibiting a varied range of pharmacological properties. In this study, the first synthesis and biological investigation of the new abietane-diterpenoid (+)-4-epi-liquiditerpenoid acid (8a) together with several of its analogs Citation: González-Cardenete, M.A.; are reported. The compounds were generated from the readily available methyl callitrisate (7), which Rivas, F.; Basset, R.; Stadler, M.; was obtained from callitrisic acid present in Moroccan Sandarac resin. A biological evaluation was Hering, S.; Padrón, J.M.; Zaragozá, conducted to determine the effects of the different functional groups present in these molecules, R.J.; Dea-Ayuela, M.A. Biological Profiling of Semisynthetic providing basic structure–activity relationship (SAR) elements. In particular, the ferruginol and C19-Functionalized Ferruginol and sugiol analogs compounds 10–16 were characterized by the presence of a phenol moiety, higher Sugiol Analogues. Antibiotics 2021, 10, oxidization states at C-7 (ketone), and the hydroxyl, methyl ester or free carboxylic acid at C19. 184. https://doi.org/10.3390/ The biological profiling of these compounds was investigated against a panel of six human solid antibiotics10020184 tumor cell lines (HBL-100, A549, HeLa, T-47D, SW1573 and WiDr), four parasitic Leishmania species (L. donovani, L. infantum, L. guyanensis and L. amazonensis) and two malaria strains (3D7 and K1). Academic Editor: Yasunori Yaoita Furthermore, the capacity of the compounds to modulate gamma-aminobutyric acid type A (GABAA) receptors (α1β2γ2s) is also described. A comparison of the biological results with those previously Received: 25 January 2021 reported of the corresponding C18-functionalized analogs was conducted. Accepted: 10 February 2021 Published: 12 February 2021 Keywords: abietane; callitrisic acid; diterpenoid; antiproliferative activity; GABAA receptor modula- tors; antimalarial activity Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Chemical diversity in natural products widely attracts scientific attention to find potential therapeutic agents like anticancer drugs from natural sources. Around 79% of commercial anticancer drugs are either natural products (NPs), directly derived from NPs Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. or inspired in NPs structures [1]. NPs are also sources of novel and selective agents for This article is an open access article the treatment of parasitic diseases. Currently, many compounds from plant sources have distributed under the terms and displayed potential antileishmanial activity; however, none of them have yet undergone conditions of the Creative Commons clinical trials [2]. Attribution (CC BY) license (https:// Abietane diterpenoids are naturally occurring metabolites isolated from a large va- creativecommons.org/licenses/by/ riety of terrestrial plants that show a wide range of promising biological activities [3,4]. 4.0/). These compounds are characterized by a tricyclic ring system. For example, the phenol Antibiotics 2021, 10, 184. https://doi.org/10.3390/antibiotics10020184 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 184 2 of 11 Antibiotics 2021, 10, 184 2 of 11 (http://creativecommons.org/licenses These compounds are characterized by a tricyclic ring system. For example, the phenol /by/4.0/). abietane-typeabietane-type diterpenoidditerpenoid ferruginolferruginol (1)(1) (Figure(Figure1 1)) has has demonstrated demonstrated antitumor antitumor activity,activity, decreasingdecreasing non-smallnon-small cellcell lunglung cancercancer growthgrowth afterafter incitinginciting caspase-associatedcaspase-associated apoptosis.apoptosis. IntraperitonealIntraperitoneal administrationadministration of of ferruginol ferruginol considerably considerably inhibited inhibited the the growth growth of of subcuta- subcu- neoustaneous cancer cancer xenograft xenograft models models [5]. [5]. Ferruginol Ferruginol (1) (1) also also displays displays antiproliferative antiproliferative properties proper- inties human in human ovarian ovarian cancer cancer and malignant and malignant melanoma melanoma cells by cells inhibiting by inhibi cancerting cancer cell migration cell mi- andgration inducing and inducing apoptosis apoptosis [6,7], as well [6,7], as as in humanwell as thyroidin human cancer thyroid cells [cancer8]. The cells correspond- [8]. The ingcorresponding C7-oxidized C7-oxidized sugiol (2) has sugiol shown (2) inhas vitro showcytotoxicn in vitro activity cytotoxic against activity human against pancreatic human andpancreatic melanoma and tumormelanoma cell modelstumor cell [9], models antitumor [9], activityantitumor against activity EBV-EA against activation EBV-EA [acti-10], andvationin vivo[10], antitumorand in vivo properties antitumor in properties a prostate in DU145 a prosta xenograftte DU145 murine xenograft model murine [11]. Typical model semisynthetic[11]. Typical bioactivesemisynthetic abietane bioactive diterpenoids abietane are diterpenoids derived from are dehydroabietic derived from acid dehydro- (3) and dehydroabietylamineabietic acid (3) and dehydroabietylamine (4) (Figure1), also called (4) (Figure leelamine 1), also [3]. called leelamine [3]. FigureFigure 1.1. ExamplesExamples ofof bioactivebioactive abietaneabietane diterpenoidsditerpenoids 1–71–7 andand testedtested moleculesmolecules 8a,8a,and and9–16. 9–16. DehydroabieticDehydroabietic acidacid (3)(3) displaysdisplays antileishmanialantileishmanial activityactivity inin bothboth promastigotespromastigotes andand amastigotesamastigotes ofofLeishmania Leishmania amazonensis amazonensis[12 [12].]. Previously, Previously, Moreira Moreir anda and coworkers coworkers reported reported on theon the antileishmanial antileishmanial activities activities of dehydroabietic of dehydroabietic acid acid derivatives derivatives and dehydroabietylamineand dehydroabietyla- amides,mine amides, which which were capable were capable of killing of killingLeishmania Leishmania donovani donovaniamastigotes amastigotes [13,14]. [13,14]. Ferruginol Fer- (1)ruginol has also (1) shown has also promising shown antileishmanialpromising antileishmanial activity against activityL. donovani againstpromastigotes L. donovani [pro-15]. Inmastigotes addition, [15]. dehydroabietic In addition, aciddehydroabietic (3) from Boswellia acid (3) thuriferafrom Boswelliaresin has thurifera been resin reported has been as a positivereported gamma-aminobutyric as a positive gamma-a acidminobutyric type A (GABA acid Atype) receptor A (GABA modulatorA) receptor [16]. modulator Recently, we[16]. reported Recently, on we the reported synthesis on the and synthesis biological and activity biological of (+)-liquiditerpenoic activity of (+)-liquiditerpenoic acid A or abietopinoicacid A or abietopinoic acid [17]. In acid that [17]. work, In wethat synthesized work, we synthesized and studied and biologically studied (antitumor,biologically GABA(antitumor,A modulation GABAA modulation and antileishmanial) and antileishmanial) a series of ferruginol a series of analogs ferruginol functionalized analogs func- at C-18tionalized from (–)-abieticat C-18 from acid (–)-abietic via methyl acid dehydroabietate via methyl dehydroabietate (C-4 epimeric compounds (C-4 epimeric of those com- depictedpounds of in those Scheme depicted1). Despite in Scheme the important1). Despite pharmacologicalthe important pharmacological properties of properties abietane diterpenoids,of abietane diterpenoids, there is only there one commercialis only one drug,commercial ecabet, drug, composed ecabet, of abietane-derivedcomposed of abi- diterpenoidsetane-derived (ecabet diterpenoids sodium (ecabet (5) (Figure sodium1) (5) for (Figure the treatment 1) for the of treatment reflux esophagitis of reflux esoph- and peptic ulcer disease). Thus, this family of natural products offers ample opportunity for further studies due to their promising biological activities. In continuation of our research Antibiotics 2021, 10, 184 3 of 11 programs on the synthesis and biological analysis