Synthesis of aminated xanthones: exploiting chemical routes to reach for bioactive compounds

Transcription

1 Synthesis of aminated xanthones: exploiting chemical routes to reach for bioactive compounds Emília Sousa 1,2, *, Agostinho Lemos 1,, Ana Gomes 1,3, Sara Cravo 1, Madalena Pinto 1,2 1 Department of Chemical Sciences, Laboratory of rganic and Medicinal Chemistry, Faculty of Pharmacy, University of Porto, Portugal; 2 CIIMAR Interdisciplinary Centre of Marine and Environmental Research, Portugal; 2 Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Portugal. * Corresponding author: esousa@ff.up.pt 1

2 Synthesis of aminated xanthones: exploiting chemical routes to reach for bioactive compounds Graphical Abstract ne-pot? Scale-up? Greenness? i) Ullmann reaction, ii) reductive amination, Activity? Toxicity? Drug-likeness? 2 2

3 Abstract: Typically, about 90% of drug candidates are -containing, and an even higher amount are - containing. As a consequence, it is not surprising that alkylation and arylation of groups with nitrogen and oxygen emerge as major reactions to obtain bioactive compounds. Xanthones are a class of -heterocycles characterized by a dibenzo-γ-pyrone nucleus. This scaffold may be considered a privileged structure able of providing useful ligands for several types of receptors and/or enzymes targets by judicious structural modifications. In our search for potential anticancer drugs we pursuit with a hybridization approach of -containing xanthones. erein, exploiting chemical routes to reach for bioactive -containing xanthones with will be shared. The synthesis of new xanthone derivatives proceeds by both strategies and the respective strengths and weakness will be presented in a medchem perspective. Although chemical route (i) (S2 reactions and nucleophilic aromatic substitutions) provided interesting antitumor derivatives, the reductive amination (ii) furnished a library of potential p53:mdm2 inhibitors with noticeable advantages such as: high-yield reactions, one-pot conversions, aliphatic amines with low potential to form reactive metabolites. The use of a variety of (thio)xanthone building blocks, with various substituents, and different reaction conditions allowed us to develop a repertoire of -transformations. Keywords: Ullmann Coupling; Reductive Amination; Xanthones; Bioactive compouds 3

4 Introduction hydrogen bonding properties amine functional group potential for increasing solubility Top 10 Reactions * reaction no. of reactions % of all reactions -acylation to amide containing heterocycle formation arylation with Ar-X RC 2 deprotection subs with alkyl-x reductive amination Boc deprotection Suzuki cross-coupling reaction substitution other deprotection total *by Frequency in the 2008 Data Set, J. Med. Chem. 2011, 54, forming a C bond 4

5 Common approach of most medicinal chemistry programs synthesizing a common core motif useful structure-activity relationships (SAR) R1 R2 performing multiple derivatizations of this core Dibenzo-gamma-pirone Pedro, M. M.; Cerqueira, F.; Sousa, M. E.; ascimento, M. S. J.; Pinto, M. M. M. Bioorg. Med. Chem. 2002, 10, R1 C 3 C R2 C 3 C 3 C R5 R4 R3 C 3 C 3 C 3 C 3 C 3 R3 R4 C 3 C 3 C 3 C 3 R5 C 3 5

6 Two projects of hit-to-lead optimization 1. ptimization of an antitumor thioxanthone lucanthone 1-chloro-4-propoxy-9thioxanthen-9-one development of P-glycoprotein inhibitors with antitumor activity 2. ptimization of a potent inhibitor of p53-mdm2 interaction cis-imidazoline Morpholinone Piperidinone Pyrrolidine Quinolinol LEM2 Classes of known p53:mdm2 inhibitors development of hybrids 6

7 1. -Arylation with Ar-X + R(R) Cu 2, Me, 100 o C closed vessel ~ 1000 designed thioxanthones (Tx) Ullmann C cross-coupling LogP MW Amine P-glycoprotein Molecules with the best scores undreds S 3 C 3 Docking C 2 C C C S 3 C 3 C 2 S 3 C C 3 3 C 3 C C 3 Palmeira, A.; Vasconcelos, M..; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa. E. Biochem. Pharmacol. 2012, 83,

8 1. -Arylation with Ar-X C 3 2 C 3 a) Cu 2, Me, 100 o C closed vessel, 2 days C 3 3 C a) 30% a) 30% a) 50% a) 30% C3 C 3 C 3 a) 10% C 3 C 3 C 3 C 3 C 3 S C 3 2 C C 3 C 3 C 3 C 3 8

9 1. -Arylation with Ar-X a) Cu 2, Me, 100 o C closed vessel, 2 days b) Cu 2, K 2 C 3, Me closed vessel, 100 o C, 2 days c + 2 ) 10% c + 2 ) 5% b) 25% C 3 C 3 c + 2 ) 85% C 3 C 3 2 C 3 C c) 13% c) 47% S 3 C C 3 C 3 C 3 a) 30% a) 30% a) 50% a) 30% C3 C 3 c) 7% b) 75% c) 28% C 3 2 C 3 C 3 C 3 c) Cu 2, K 2 C 3, MP, MW 205 o C, 50 min c) 9% c) 21% c) 26% c) 53% C 3 c) 30% c) 65% c) 52% c) 24% a) 10% C MP= -methylpirrolidone MW= microwave

10 1. -Arylation with Ar-X Results and discussion Catalyst Amount of catalyst Ligand Base Solvent Yield (PLC) TXA1 TXMe Cu 2 5% mol K 2 C 3 Methanol trace Cu(0) 5% mol K 2 C 3 Methanol trace C 3 Methanol 26 1 CuI 10% mol K 2 C 3 Methanol C 3 Acetonitrile trace C 3 Isopropanol trace C 3 Propanol trace C 3 MP trace C 3 Water trace C 3 Ethanol 12 2 (TXEt) C 3 Formamide trace C 3 neat trace CuI 5% mol Et 3 neat trace C 3 Ethylenoglycol 10 Pd(dppf)Cl 2.C 2 Cl 2 5% mol K 2 C 3 Methanol trace Pd 2 (dba) 3 :BIAP 5% mol tbua Methanol trace n.d. Pd 2 (dba) 3 : BIAP 5% mol CsC 3 Methanol trace CuI 5% mol Picolinic acid 20% mol K 2 C 3 Methanol trace CuI 5% mol,-dimethylglicine 20% mol K 2 C 3 Methanol 43 4 CuI 5% mol,-dimethylglicine 20% mol K 2 C 3 neat 9 CuI 5% mol,-dimethylglicine 20% mol K 2 C 3 Ethylenoglycol trace CuI + Montmorillonite K10 5% mol + 10eq K 2 C 3 Methanol 16 n.d. 50% overall yield (~10g) Buchwald-artwig reaction 10

11 1. -Arylation with Ar-X 11

12 2. ptimization of a potent inhibitor of p53-mdm2 interaction Xanthone derivatives represent a priviliged scaffold for antitumor agents with the ability to activate p53 pathway aturally-occuring xanthones p53 MDM2 Gambogic acid α-mangostin Synthetic xanthones Pyranoxanthone LEM1 Formylated xanthone LEM2 M. Leão, et al. Biochemical Pharmacology 2013, 85(9), M. Leão, et al. Journal of atural Products 2013, 76 (4), p53:mdm2 12

13 Reductive Amination btaining the functionalized aldehyde was the 1st drawback for a rapid synthetic protocol 50% 35% 19% LEM2 80% 45% r.t. = room temperature, MW = microwave 40% 13

14 Reductive Amination btaining the functionalized aldehyde was the 1st drawback for a rapid synthetic protocol 50% 35% 19% LEM2 80% 45% 40% [(BMIm)BF4] = 1-butyl-3- methylimidazolium tetrafluoroborate 14

15 Reductive Amination LEM2 Table 1. Reaction yields (%) of the new aminoxanthone derivatives* LEM2 Compounds Yield (%) a) MP-CB 3, C 3 C, C 3, r.t., overnight b) STAB, C 3 C, TF, r.t., overnight Compounds Yield (%) ALX1 56 ALX5 40 Compounds Yield (%) ALX2 57 ALX6 63 ALX9 35 ALX3 70 ALX7 68 ALX10 36 ALX4 41 ALX8 62 ALX11 58 MP-CB 3 = Solid-supported cyanoborohydride, STAB = Sodium triacetoxyborohydride, TF = tetrahydrofuran, r.t. = room temperature *Due to confidentiality issues, the compounds are not shown. 15

16 Reductive Amination 16

17 Conclusions a variety of (thio)xanthone building blocks, pendent functionalities, and different reaction conditions allowed us to develop a repertoire of -transformations Importance the use of enabling techniques in synthesis Microwave irradiation ew solvents Catalysis 17

18 Acknowledgments national funds from FCT Fundação para a Ciência e a Tecnologia under the project CEQUIMED PEst- E/SAU/UI4040/2014 and ERDF through CMPETE and national funds from FCT, PEst-C/MAR/LA0015/