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Octahydroquinoxalin-2 (1H)-One-Based Aminophosphonic

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Octahydroquinoxalin-2 (1H)-One-Based Aminophosphonic materials Article Octahydroquinoxalin-2(1H)-One-Based Aminophosphonic Acids and Their Derivatives—Biological Activity towards Cancer Cells Jakub Iwanejko 1 , El˙zbietaWojaczy ´nska 1,* , Eliza Turlej 2 , Magdalena Maciejewska 2 and Joanna Wietrzyk 2 1 Faculty of Chemistry, Wrocław University of Science and Technology, Wybrze˙zeWyspia´nskiego 27, 50-370 Wrocław, Poland; [email protected] 2 Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland; [email protected] (E.T.); [email protected] (M.M.); [email protected] (J.W.) * Correspondence: [email protected]; Tel.: +48-71-320-2410 Received: 19 March 2020; Accepted: 19 May 2020; Published: 22 May 2020 Abstract: In the search for new antitumor agents, aminophosphonic acids and their derivatives based on octahydroquinoxalin-2(1H)-one scaffold were obtained and their cytotoxic properties and a mechanism of action were evaluated. Phosphonic acid and phosphonate moieties increased the antiproliferative activity in comparison to phenolic Mannich bases previously reported. Most of the obtained compounds revealed a strong antiproliferative effect against leukemia cell line (MV-4-11) with simultaneous low cytotoxicity against normal cell line (mouse fibroblasts-BALB/3T3). The most active compound was diphenyl-[(1R,6R)-3-oxo-2,5-diazabicyclo[4.4.0]dec-4-yl]phosphonate. Preliminary evaluation of the mechanism of action showed the proapoptotic effect associated with caspase 3/7 induction. Keywords: aminophosphonate; imine; antiproliferative activity; cell cycle; mitochondrial membrane potential 1. Introduction At present, our attention is focused on the COVID-19 pandemic and there is a tendency to neglect the civilization diseases which however remain the main reason for mortality worldwide. In particular, recently published data have shown that cancers are some of the leading causes of death in Poland, with prostate cancer (almost 20% of patients) and lung cancer as the most common in the male population. The third cause of male mortality is colorectal (colon and rectum) cancer. In the female population, lung cancer dominates, followed by breast and colorectal cancer. Among young Poles, leukemias, lymphomas and brain cancers predominate and account for about 56% of cases [1]. Anticancer drug design is a challenging field with a continuous demand for new, selective and non-toxic agents for treatment [2]. Among various classes of compounds, aminophosphonic acids and their derivatives meet these requirements. Due to their similarities to α-amino acids and a wide range of applications, α-aminophosphonic acids are continuously gaining importance in organic synthesis. So far, a number of applications such as antiviral [3,4] or cytotoxic agents [5,6], enzyme inhibitors [7,8] immune system activators [9] or antibacterial activities [10] have attracted considerable attention. The importance of these acids and their derivatives in the search for new pharmaceutical uses has been extensively discussed in numerous review articles [11–14]. The α-aminophosphonic acid and its derivatives pose a crucial role in a variety of biological activities (Figure1), including cytotoxic properties. Materials 2020, 13, 2393; doi:10.3390/ma13102393 www.mdpi.com/journal/materials Materials 2020, 13, 2393 2 of 16 Materials 2020, 13, x FOR PEER REVIEW 2 of 16 Figure 1.1. AminophosphonicAminophosphonic acid acid and and aminophosphonates aminophosphonates of potential of potential medical medical importance. importance. (A) AMPA (A) (AMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor acid) antagonistreceptor [antagonist15]; (B) antimicrobial [15]; (B) antimicrobialaminophosphonate aminophosphonate [16]; (C) anti-HIV [16]; (C agent) anti- [HIV17]; agent (D) cytotoxic[17]; (D) agentcytotoxic against agent humanagainst cervicalhuman cervicalcarcinoma carcinoma [18]. [18]. Aminophosphonates bearing bearing an an N-Nheterocyclic-heterocyclic fragment fragment have have received received particular particular attention attention over α theover last the years last among years among other potential other potential anticancer anticancer agents [1 agents9–22]. [α19-Amino–22]. acids-Amino and acidstheir esters and their are consideredesters are consideredversatile pharmacophores, versatile pharmacophores, known for knownantitumor for antitumoractivity [23]. activity The group [23]. Theof Nikalje group α successfullyof Nikalje successfully coupled indole coupled-2,3-diones indole-2,3-diones with α-aminophosphonates, with -aminophosphonates, which led whichto new led sel toective, new antiproliferativeselective, antiproliferative compounds, compounds, analogues analoguesof commercially of commercially available drugs, available orantinib drugs, orantiniband sunitinib and [24].sunitinib In another [24]. In noteworthy another noteworthy example, example, Huang and Huang co-workers and co-workers proved provedthat the that incorporation the incorporation of an aminophosphonateof an aminophosphonate moiety moiety to irinotecan, to irinotecan, a chemotherapeutic a chemotherapeutic agent, increased agent, increased the cytotoxicity the cytotoxicity against certainagainst certaincancer cancercell lines cell [25]. lines The [25]. fact The of fact their of their negligible negligible mammalian mammalian toxicity toxicity [12] [12 ]testifies testifies to to the usefulness of these compounds in drug discovery research. A convenient route to this class of compounds is the P Pudovikudovik reaction reaction—a—a nucleophilic addition of dialkyl phosphites to imines [[26].26]. Another approach, Kabachnik Kabachnik–Fields–Fields one one-pot-pot three three-component-component protocol, requires an amine, a carbonyl compound and an alkyl phosphite, however however,, it fails with electronelectron-deficient-deficient amin amineses [27]. [27]. Most Most of ofthe the reported reported reactions reactions are base are base-- or acid or- acid-catalyzed,catalyzed, and non and- catalyzednon-catalyzed procedures procedures remain remain scarce scarce [28]. A [ 28recent]. A review recent covers review the covers reactions the reactions and synthetic and syntheticmethods formethods aminophosphonates for aminophosphonates [29]. [29]. In our previous research, we reported on the synthesissynthesis and antiproliferative action of novel phenolic adducts adducts of of bicyclic bicyclic imine imine 1 1(Scheme (Scheme 1)1)[ [30].30 ].Two Two phenolic phenolic Mannich Mannich bases bases were were found found to be to comparativelybe comparatively active active to cisplatin to cisplatin with with a noticeable a noticeable increase increase of selectivity of selectivity against against cancer cancer cell lines cell lines(one (oneof them of them shown shown on onthe thescheme). scheme). The The tested tested compounds compounds exhibit exhibit a aresemblance resemblance to to bioactive diketopiperazines inin theirtheir bicyclicbicyclic fragments.fragments. OurOur new new goal goal was was to to synthesize synthesize phosphorus phosphorus analogs analogs of ofthese these structures structures and and evaluate evaluate their their cytotoxicity cytotoxicity against against cancer cancer cell lines. cell Among lines. Amo a varietyng a of variety synthetic of syntheticmethods formethods heterocyclic for heterocyclic aminophosphonates aminophosphonates formation formation [31], our group [31], hasour focusedgroup has on focused a convenient on a convenientnucleophilic nucleophilic addition of addition dialkyl phosphites of dialkyl tophosphites a cyclic imine. to a cyclic imine. Bearing in mind the remarkable precedents of improving the efficacy efficacy of cytotoxicity against cancer cell lines by insertion of aminophosphonate moiety moiety and and the the results results of of our our previous previous research, research, we directed our examinations toward the evaluation of antiproliferative properties of the phosphonic derivatives of octahydroquinoxali octahydroquinoxalin-2(1n-2(1H)-one.)-one. Materials 2020, 13, 2393 3 of 16 Materials 2020, 13, x FOR PEER REVIEW 3 of 16 Scheme 1. SynthesisSynthesis of of phenolic phenolic Mannich Mannich bases bases and aminophosphonates. In our studies of the aminophosphonicaminophosphonic acids and aminophosphonates MV4 MV4-11-11 (B phenotypic myelomonocytic) cell cell line line carrying carrying translocation translocation t(4;11) t(4;11) was was used. used. MV4 MV4-11-11 corresponds corresponds to AML to AMLM5b (accordingM5b (according to the to thepreviously previously used used French French–American–British–American–British (FAB) (FAB) classification classification based based on on the morphology features of the cells). Such an AML AML subtype subtype is characterized characterized by a tendency to occupy the gums, lymph nodes and skin [32]. [32]. MV4 MV4-11-11 cell cell line line gr growthowth in suspension has about 50 h doubling time that that makes makes it it a a good good and and a a sensitive sensitive model model for for searching searching for for new new synthesized synthesized compounds compounds against against leukemia cells. 2. Materials and Methods 2. Materials and Methods 2.1. Compounds and General Considerations 2.1. Compounds and General Considerations All the reagents and solvents were purchased from commercial suppliers and used without All the reagents and solvents were purchased from
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