The Therapeutic Potential of Migrastatin-Core Analogs for the Treatment of Metastatic Cancer
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molecules Review The Therapeutic Potential of Migrastatin-Core Analogs for the Treatment of Metastatic Cancer Ernest Giralt 1,2 and Daniele Lo Re 1,* 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, C/Baldiri Reixac 10, Barcelona E-08028, Spain; [email protected] 2 Department of Organic Chemistry, University of Barcelona, Marti i Franques 1-11, Barcelona E-08028, Spain * Correspondence: [email protected]; Tel.: +34-635-060-534 Academic Editors: Dong-Kug Choi and Palanivel Ganesan Received: 11 January 2017; Accepted: 2 February 2017; Published: 9 February 2017 Abstract: Tumor metastasis is a complex process in which cells detach from the primary tumor and colonize a distant organ. Metastasis is also the main process responsible for cancer-related death. Despite the enormous efforts made to unravel the metastatic process, there is no effective therapy, and patients with metastatic tumors have poor prognosis. In this regard, there is an urgent need for new therapeutic tools for the treatment of this disease. Small molecules with the capacity to reduce cell migration could be used to treat metastasis. Migrastatin-core analogs are naturally inspired macrocycles that inhibit pathological cell migration and are able to reduce metastasis in animal models. Migrastatin analogs can be synthesized from a common advanced intermediate. Herein we present a review of the synthetic approaches that can be used to prepare this key intermediate, together with a review of the biological activity of migrastatin-core analogs and current hypotheses concerning their mechanism of action. Keywords: diverted total synthesis; natural products; cancer metastasis 1. Introduction Cell migration is a physiological process and a central feature in embryonic development, tissue repair and immune cell function. Importantly, cell migration is also responsible for angiogenesis, tumor invasion, and metastasis [1]. The cytoskeleton drives cell migration and a key cytoskeletal component is Actin. Several targets have been proposed for the inhibition of Actin dynamics, including the following: (1) actin (e.g., phalloidin (1) an F-actin stabilizer or cytochalasin D (2), an F-actin destabilizer); (2) tubulin and microtubule (e.g., taxol (3), a microtubule stabilizer or vincristine (4), a microtubule destabilizer); (3) actin-binding proteins (ML-7 (5), a myosin light chain kinase inhibitor); and (4) upstream signaling molecules (e.g., Y27632 (6), a Rho-kinase inhibitor) [2] (Figure1). Migrastatin (7) is a natural product that was originally isolated from Streptomyces sp. MK-929-43F1 [3,4] and later found in fermentation broths of Streptomyces platensis [5]. Migrastatin comprises a 14-membered ring macrolactone incorporating two E bonds and one Z double bond, together with three contiguous stereocenters and a pendant alkyl gluturamide side chain. It has been reported that migrastatin inhibits cell migration [3,4], suppresses multi-drug resistance [6], and antagonizes muscarinic acetylcholine receptor [7]. Molecules 2017, 22, 198; doi:10.3390/molecules22020198 www.mdpi.com/journal/molecules Molecules 2017, 22, 198 2 of 26 Molecules 2017, 22, 198 2 of 26 Molecules 2017, 22, 198 2 of 26 Targeting Actin directly Targeting microtubule Targeting Actin-binding protein OH Targeting ActinO directly Targeting microtubuleO Targeting Actin-binding H HN O N OH O O OH protein N O H OH O O N HN H HN NH O NH O O O O N OH O O OH S S N O O N H O O O H N HN H OH O O N NHNHO O NHOHO O O S N O S HO H O O N O O H O I HHOO O N NH O OH OH O PhalloidinN (1) Taxol (3) ML-7 (5) HO H O OF-Actin stabilizer Microtubule stabilizerO Myosin light chain kinaseI inhibitor HO Phalloidin (1) Taxol (3) ML-7 (5) F-Actin stabilizer Microtubule stabilizer Myosin light chain kinase inhibitor OH Targeting upstream signaling OH OH Targeting upstream H H N N O HN signaling OH O N HN H H H O H N H O N N O OAc O HN OAc OH H O O O OH N HN H H NH2 O OMe H O N CytochalasinOAc D (2) O Vincristine (4) OAc Y-27632 (6) OH OH H F-Actin destabilizer MicrotubuleO destabilizerO Rho-kinase inhibitorNH OMe 2 Cytochalasin D (2) Vincristine (4) Y-27632 (6) F-Actin destabilizer Microtubule destabilizer Rho-kinase inhibitor Figure 1. Small-molecule inhibitors of cell mobility. Figure 1. Small-molecule inhibitors of cell mobility. In 2003, Danishefsky andFigure co-workers 1. Small-molecule described inhibitors the first of cell total mobility. synthesis of migrastatin [8]. One Inyear 2003, later, Danishefsky the same group and co-workersdemonstrated described that ablation the first of the total glutaramide synthesis ofside migrastatin chain increases [8]. One the year later,biological the sameIn 2003, activity group Danishefsky demonstratedof migrastatin and co-workers analogs that ablation 1000-fold described of with the th glutaramide erespect first total to natural synthesis side migrastatin chain of migrastatin increases [9]. They the [8]. found biologicalOne activityyearthat of simplerlater, migrastatin the analogs same analogs groupat nanomolar demonstrated 1000-fold concentrations with that ablation respect were oftoable the natural to glutaramide inhibit migrastatin cell sidemigration chain [9]. in Theyincreases 4T1 foundmouse the that simplerbiologicalmammary analogs activity tumor at nanomolar cells.of mi Danishefskygrastatin concentrations analogs demonstrated 1000-fold were able thatwith tomigrastatin respect inhibit to cell natural and migration simplified migrastatin in migrastatin 4T1 [9]. mouse They analogs found mammary that simpler analogs at nanomolar concentrations were able to inhibit cell migration in 4T1 mouse tumorcould cells. be Danishefsky easily synthesized demonstrated from a common that migrastatin advanced andintermediate simplified 8. migrastatinThis result highlights analogscould the be mammarypotential of tumor diverted cells. total Danishefsky synthesis demonstrated drug discovery that (Figure migrastatin 2). and simplified migrastatin analogs easilycould synthesized be easily fromsynthesized a common from advanceda commonintermediate advanced intermediate8. This result 8. This highlights result highlights the potential the of divertedpotential total of synthesis diverted drugtotal synthesis discovery drug (Figure discovery2). (Figure 2). Figure 2. Diverted total synthesis approach for the preparation of migrastatin (7) and truncated analogs MGSTA-1,6 from a common advanced intermediate (8). IC50 values (in parentheses) in Figure 2. Diverted total synthesisa approach for the preparation ofb migrastatin (7) and truncated Figureboyden 2. Diverted chamber total assays synthesis against approach 4T1 mouse for mammary the preparation cancer ofand migrastatin A549 human (7) andlung truncatedcancer cells. analogs analogs MGSTA-1,6 from a common advanced intermediate (8). IC50 values (in parentheses) in MGSTA-1,6 from a common advanced intermediate (8). IC values (in parentheses) in boyden boydenSeveral chamber groups have assays been against involved a 4T1 mousein the preparationmammary cancer of 8 (Figure and50 b A549 3 and human table 1)lung [8–14]. cancer The cells. synthesis chamber assays against a 4T1 mouse mammary cancer and b A549 human lung cancer cells. and the biological activity of migrastatin (7) and migrastatin analogs were covered by Reymond and CossySeveral in 2008 groups [15]. haveThe aim been of involved this review in the is preparation to discuss theof 8 recent(Figure synthetic 3 and table approaches 1) [8–14]. The used synthesis for the Severaland the biological groups haveactivity been of migrastatin involved (7 in) and the migrastatin preparation analogs of 8were(Figure covered3 and by Reymond Table1)[ and8 –14]. The synthesisCossy in 2008 and [15]. the biologicalThe aim of activitythis review of migrastatinis to discuss the (7) recent and migrastatin synthetic approaches analogs wereused coveredfor the by Reymond and Cossy in 2008 [15]. The aim of this review is to discuss the recent synthetic approaches Molecules 2017, 22, 198 3 of 26 Molecules 2017, 22, 198 3 of 26 usedpreparation for the preparation of 8, together of 8 ,with together new findings with new that findings provide thatinsight provide into the insight anti-metastatic into the potential anti-metastatic of potentialmigrastatin of migrastatin analogs and analogs their targets. and their targets. FigureFigure 3. Synthetic 3. Synthetic strategies strategies for for thethe preparationpreparation of of advanced advanced intermediate intermediate 8. 8. Table 1. Synthetic key aspects for the preparation of advanced precursor 8. Table 1. Synthetic key aspects for the preparation of advanced precursor 8. Year Authors n0 Steps Overal Yield Key Steps Notes Reference Overal LACDAC reaction, Multi-gram scale Year2004 AuthorsDanishefsky et al.n0 Steps10 22% Key Steps Notes[8,9,16] Reference Yield Ferrier rearrangement synthesis Stereoselective 2006 Cossy et al. 11 (+4) a 11% LACDAC reaction, - [10] 2004 Danishefsky et al. 10 22% crotylmetalation, RCM Multi-gram scale synthesis [8,9,16] Ferrier rearrangement Entry to StereoselectiveStereoselective 2006 Cossy et al. 11 (+4) a 11% isomigrastatin-[ 10] 2007 Cossy et al. 11 (+4) a 35% crotylmetalation,crotylmetalation, RCM Still- [17] analogues, gram StereoselectiveGennari olefination Entry toscale isomigrastatin 2007 Cossy et al. 11 (+4) a 35% crotylmetalation, Still-Gennari [17] Evans aldol analogues, gram scale olefination condensation and Entry to 2006 Lqbal et al. 12 8% Evans aldoldistereoselective