Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2020 Feb 7;11(5):846–851. doi: 10.1021/acsmedchemlett.9b00643

Synthesis and Antiproliferative Activity of Nitric Oxide-Donor Largazole Prodrugs

Matteo Borgini †, Claudio Zamperini †,‡, Federica Poggialini †, Luca Ferrante ∥, Vincenzo Summa ⊥, Maurizio Botta †,‡,§, Romano Di Fabio ∥,⊥,*
PMCID: PMC7236235  PMID: 32435394

Abstract

graphic file with name ml9b00643_0010.jpg

The marine natural product Largazole is the most potent Class I HDAC inhibitor identified to date. Since its discovery, many research groups have been attracted by the structural complexity and the peculiar anticancer activity, due to its capability to discriminate between tumor cells and normal cells. Herein, we discuss the synthesis and the in vitro biological profile of hybrid analogues of Largazole, as dual HDAC inhibitor and nitric oxide (NO) donors, potentially useful as anticancer agents. In particular, the metabolic stability of the modified thioester moiety of Largazole, bearing the NO-donor function/s, the in vitro release of NO, and the antiproliferative activity in tumor cell lines are presented.

Keywords: Largazole, HDAC, nitric oxide, cancer, prodrug

Largazole is a potent and selective Class-I deacetylase (HDAC) inhibitor, isolated in 2008 from marine cyanobacteria Symploca sp.,1 that showed a broad-spectrum growth-inhibitory activity against epithelial and fibroblastic tumor cell lines and a remarkable differential cytotoxicity profile over nontransformed cells.1−3 The structure of Largazole is characterized by the presence of an intriguing planar 16-membered depsipeptide core bearing a metabolically labile thioester side-chain, which, upon hydrolytic cleavage, liberates Largazole-thiol, the bioactive HDAC inhibitor species (Figure 1).4

Figure 1.

Figure 1

Open in a new tab

Chemical structures of Largazole, Largazole-SH, and Vorinostat (SAHA).

HDACs are a family of epigenetic enzymes that catalyze the deacetylation of ε-N-acetyl lysine in H3 and H4 histone tails, resulting in a tighter chromatin structure that inhibits transcription. Eighteen different HDAC isoforms have been identified to date, subdivided into 4 classes (I to IV): class I (HDAC-1, HDAC-2, HDAC-3, HDAC-8), class IIa (HDAC-4, HDAC-5, HDAC-7, HDAC-9), class IIb (HDAC-6, HDAC-10), class III (Sirtuin-1, Sirtuin-2, Sirtuin-3, Sirtuin-5, Sirtuin-6, Sirtuin-7), and Class IV (HDAC-11). With the only exception of Sirtuins (class III), the deacetylation of histone proteins is typically mediated by a Zn2+-dependent mechanism.5−9

The inhibition of HDAC was found to induce cancer cell cycle arrest and cell death, reduce angiogenesis, and modulate immune response. In particular, the pan-HDAC inhibitor of class I, II, and IV SAHA (suberoylanilide hydroxamic acid, Vorinostat, Zolinza),10 depicted in Figure 1, was the first FDA-approved HDAC inhibitor for the treatment of refractory primary cutaneous T-cell lymphoma (CTCL).11 Luesch and co-workers demonstrated that the antiproliferative activity of Largazole was specifically due to the inhibition of HDAC enzymes targeting Ac-H3 (Lys 9/14).1 More recently, Largazole was hypothesized to play a relevant role also in the control of osteogenesis12 and in liver fibrosis.13

In terms of structure–activity relationship (SAR) and mode of action, the X-ray analysis of the cocrystal structure of the complex HDAC-8 and Largazole demonstrated that the 16-membered depsipeptide core interacted as capping moiety with the surface rim of the enzyme, while the terminal thiol group, present in the pendant “warhead” of the macrocycle core, chelated the catalytic Zn2+-containing catalytic domain of the enzyme with an ideal coordination geometry.14 In fact, any attempt to modify the thiol moiety resulted in the significant loss of activity.15,16 Largazole shares some structural similarities with FK288 (Romidepsin, Istodax, Figure 1),17,18 a Class I HDAC inhibitor approved in 2009 by the FDA for the of treatment of CTCL. This naturally occurring depsipeptide, upon metabolic reduction of the disulfide bond, releases the pharmacologically active species bearing the Zn2+-binding thiol group.

Over the last decades, many research groups investigated the anticancer property of nitric oxide (NO) and its capability to overcome tumor cell resistance to conventional treatments.19 NO is an endogenous and chemically reactive free radical gas, known as the smallest signaling molecule in living organisms. It is produced in mammals from amino acid l-arginine, oxygen, and the cofactor tetrahydrobiopterin, by three distinct NO synthase isozymes, namely: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS).20 NO is involved in the regulation of a plethora of physiological and pathological biochemical pathways in organs and tissues.20−22 In particular, NO plays a key role as neurotransmitter at the synapsis level23 acting as a key mediator of learning, sleep, and feeding in the central nervous system. In addition, among other functions, it controls the vascular tone, regulates gene transcription and mRNA translation, and produces post-translational modifications of proteins. Of note, NO shows dichotomous differential cellular response by distinct concentrations, either facilitating cancer events, including angiogenesis, apoptosis, and metastasis23 or, at high concentrations (>200 nM), acting as a potent an anticancer agent.19,23−26

In light of this evidence over the last years dual NO donors/HDAC inhibitors emerged as novel anticancer chemical entities, potentially more efficacious than selective HDAC inhibitors, owing to the capability of NO to specifically modulate the function of some HDAC isoforms.27 In particular, it has been found that class I HDAC- 2 is structurally modified by direct reaction with NO, either S-nitrosylation or Tyr-nitration reaction, or shuttled into the cell nucleus through the activation of protein phosphatase 2A.28,29

The first mixed NO-donor/HDAC inhibitor was reported in 2013, as a compound potentially useful for the treatment of cardiac hypertrophy and wound healing.30 This novel hybrid molecule, obtained from the known HDAC inhibitor Entinostat by the introduction of a constitutive NO-donor furoxan moiety, showed a similar HDAC inhibitory profile as Entinostat but an additive myogenic differentiation activity. Since then, several hybrid NO-donor/HDAC inhibitor derivatives, potentially useful as anticancer agents, have been reported in the literature.31 In particular, hybrid Doxorubicin-NO donors were found to be active against Doxorubicin-resistant human colon cancer cells (HT29-dx).32 In addition, interesting results were obtained joining NO-donor moieties with anticancer platinum derivatives33 and PepT1 inhibitors.34 Finally, some different hybrid HDAC inhibitor-NO donors exhibited an enhanced cytotoxic activity compared to HDAC inhibitors.35

Owing to this evidence, our aim was to obtain novel Largazole derivatives bearing one or more NO-donor functions at the metabolically labile thioester chain. These novel types of HDAC inhibitors, exploiting the prodrug character of the thioester moiety of Largazole, upon enzymatic hydrolysis would have efficiently released Largazole-thiol, the pharmacologically active species as HDAC inhibitor, and depending on the specific functionalization of the aliphatic thioester chain, produced one or more equivalents of NO (Figure 2).

Figure 2.

Figure 2

Open in a new tab

Chemical structures of Largazole analogues 1 and 2.

To this aim, compounds 1 and 2 were synthesized and then sequentially evaluated in terms of capability to release NO in vitro, metabolic stability, and antiproliferative activity in tumor cell lines with respect to Largazole.

The retrosynthetic analysis of compounds 1 and 2, shown in Figure 3, suggested the disconnection of the olefin moiety, that could have then been obtained by cross-metathesis reaction between the known synthetic Largazole intermediate 3 and the terminal olefin derivative bearing suitable nitrate group/s.

Figure 3.

Figure 3

Open in a new tab

Retrosynthetic approach for the synthesis of NO-donor Largazole derivatives 1 and 2.

Compound 3 was prepared by condensation of fragments A and B, as depicted in Figure 3, following the same synthetic sequence reported in the literature.36 However, to obtain intermediate 3 in multigram scale, we specifically focused our attention on the optimization of the synthesis of fragment A (Scheme 1), which was efficiently prepared in seven synthetic steps and 63% total yield from commercially available N-Boc glycine 4. In particular, intermediate 6, synthesized in two steps and 82% yield from 4, was transformed into the corresponding thiazole derivative with 3-bromopyruvic acid in THF at 50 °C, to get the corresponding free amino derivative, which was reprotected as N-Boc, affording 7 in 96% yield over two steps.

Scheme 1. Optimized Synthesis of Fragment A.

Scheme 1

Open in a new tab

Reagents and conditions: (a) isobutyl chloroformate, N-methyl morpholine, NH4OH, THF, −20 °C to r.t., 1 h; (b) Lawesson’s reagent, CH2Cl2, r.t., 15 h; (c) 3-bromopyruvic acid, THF, 50 °C, 1 h; (d) Boc2O, 1N NaOH, dioxane, r.t., 40 min; (e) TFAA, diisopropylethyl amine, CH2Cl2, 0 °C, 1 h; (f) TEA, MeOH, reflux, 7 h.

Then, its carboxylic function was smoothly transformed into the corresponding nitrile derivative 9  which was condensed with α-methyl cysteine 10, prepared from cysteine as reported in the literature, affording target fragment A in 94% yield. The NO-donor thioester olefin derivative 14 was synthesized as shown in Scheme 2.

Scheme 2. Synthesis of the Mono-nitrate Olefin Derivative 14.

Scheme 2

Open in a new tab

Reagents and conditions: (a) AgNO3, dry CH3CN, 70 °C, 2 h. (b) Lawesson’s reagent, CH2Cl2, 60 °C, 10 min, MW. (c) 4-bromo-1-butene, K2CO3, acetone, 0 to 20 °C, 30 min.

5-bromovaleric acid 11 was reacted with AgNO3 in dry CH3CN at 70 °C for 2 h to obtain intermediate 12, which was then transformed into the corresponding thiocarboxylic acid derivative 13 by Lawesson’s reagent in a microwave reactor at 60 °C. The final alkylation reaction with 4-bromo-1-butene afforded the target olefin derivative 14 in 85% yield.

The following key intermolecular cross-metathesis reaction between intermediate 3 and compound 14, performed with Grubbs second generation ruthenium-based catalyst (Scheme 3), gave the target Largazole thioester analogue 1, although only in 26% yield, due to the competitive homodimeric coupling reaction of the olefin derivative 14, as confirmed by the isolation of a large amount of unreacted olefin derivative 3, after purification by flash chromatography.

Scheme 3. Cross-metathesis Reaction.

Scheme 3

Open in a new tab

Reagent and conditions: Grubbs II, dry CH2Cl2, 90 °C, 16 h.

As far as the synthesis of the corresponding bis-nitrate derivative 2 is concerned, the same synthetic sequence used from the preparation of 14 was initially attempted (Scheme 4). 4-Pentenoic acid 15 was protected as p-nitrophenol (PNP) ester. The following bromination reaction of intermediate 16 afforded compound 17 in 81% yield, which was easily converted into the corresponding bis-nitrate compound 18 in the presence of AgNO3 in CH3CN at 70 °C for 24 h. After the basic hydrolysis of the ester group, the resulting carboxylic acid 19 was transformed into the chemically labile thiocarboxylic acid derivative 20, which was rapidly alkylated with 4-bromo-1-butene, to obtain compound 21 in 23% yield over two steps (Scheme 4). The following intermolecular cross-metathesis reaction with Largazole intermediate 3, using the same reaction conditions set up for the synthesis of compound 1, afforded this time only the side product derived from homodimeric coupling reaction of the olefin derivative 21.

Scheme 4. Synthesis of Bis-nitrate Olefin 21.

Scheme 4

Open in a new tab

Reagents and conditions: (a) DIC, DMAP, CH2Cl2, 0 °C to r.t., 1 h; (b) Br2, CCl4, 0 °C to r.t., 10 min; (c) AgNO3, dry CH3CN, 70 °C; 24 h. (d) NaOH 2 N, THF/EtOH, 0 °C, 30 min; (e) Lawesson’s reagent, CH2Cl2, 60 °C, 15 min, MW; (f) 4-bromo-1-butene, K2CO3, THF/MeOH, 0 °C to r.t., 1 h.

Due to this unexpected result, to obtain compound 2, the synthetic approach was significantly modified (Scheme 5).

Scheme 5. Synthesis of Compound 2.

Scheme 5

Open in a new tab

Reagents and conditions: (a) triphenylmethanethiol, DIC, DMAP, dry CH2Cl2, 0 °C to r.t., 4 h; (b) TFA, triethylsilane, dry CH2Cl2, 0 °C to r.t., 1 h; (c) 4-bromo-1-butene, Grubbs II, dry CH2Cl2, 90 °C, 16 h; (d) K2CO3, acetone, 0 °C to r.t., 5 h.

To this aim, the bis-nitrate carboxylic acid derivative 19 was transformed into the corresponding S-trityl thiocarboxylic ester derivative 22. The following deblocking reaction of the S-trityl protecting group, with TFA and triethylsilane in CH2Cl2 at room temperature for 1 h, afforded the corresponding chemically labile thiocarboxylic acid 23, which was rapidly reacted with the bromo derivative 24, smoothly synthesized from intermediate 3 by metathesis reaction with 4-bromo-1-butene in 42% yield, to get title compound 2.

Largazole derivatives 1 and 2 were initially characterized in terms of capability to release NO, using the Griess method.37 As shown in Figure 4, in the assay conditions, both compounds spontaneously produced NO.

Figure 4.

Figure 4

Open in a new tab

NO release assay. Compounds 1 (A) and 2 (B) were incubated at 0.1 mM concentration in 50 mM phosphate buffer (pH = 7.4) at 37 °C, both in the absence and in the presence of l-cysteine (0.5 mM and 5 mM). The yield of NO2– is expressed as % with respect to the initial concentration of compound at 1 h, 5 h, and 24 h, respectively. The reported values are the average of three independent experiments.

As expected, the NO production was amplified in the presence of increasing concentration of l-cysteine. The NO release was obviously more abundant for compound 2 than compound 1, due to the presence of two NO-donor groups.

Once ascertained the capability of both compounds to efficiently release NO, their antiproliferative activity was evaluated against U-2OS (human osteosarcoma cell), Caco-2 (human colorectal adenocarcinoma cell), and IMR-32 (human neuroblastoma cell), using the parent compound Largazole as internal control. As shown in Table 1, compounds 1 and 2 showed a concentration and time-dependent inhibitory activity against tumor cell growth. In particular, as per the antiproliferative activity in the U-2OS cell lines, both compounds showed a relevant additive effect at 24 h with respect to the antiproliferative activity of Largazole, whereas, at 48 and 72 h, the antiproliferative effect was similar to that of Largazole. The greater antiproliferative activity of compound 2 vs compound 1 at 24 h (pEC50 = 6.33 vs 5.71, respectively) is most likely due to the higher production of NO by compound 2 with respect to compound 1.

Table 1. Cytotoxicity of Largazole, 1, and 2 against U-2OS, Caco-2, and IMR-32 Cell Line.

    Compounda
Cell line Time Largazole 1 2
U-2OS 24 h 4.69 ± 0.12 5.71 ± 0.15 6.33 ± 0.10
48 h 6.43 ± 0.15 6.51 ± 0.15 6.13 ± 0.20
72 h 6.48 ± 0.10 6.77 ± 0.09 6.00 ± 0.70
CaCo-2 24 h >2.0 4.95 ± 0.19 5.04 ± 0.24
48 h 6.12 ± 0.21 7.42 ± 0.14 8.25 ± 0.22
72 h 7.84 ± 0.09 8.09 ± 0.16 8.35 ± 0.16
IMR-32 24 h 7.46 ± 0.16 7.82 ± 0.17 7.53 ± 0.12
48 h 7.52 ± 0.14 7.71 ± 0,17 7.21 ± 0,18
72 h 7.91 ± 0.08 7.92 ± 0.06 7.30 ± 0.14
Open in a new tab
a

EC50 were determined as described in the Supporting Information; they are the average value of n = 3 independent experiments ± SEM.

This general trend is even more evident in the Caco-2 cell line, in which the improved antiproliferative activity of both compounds was more pronounced than that shown by Largazole at 24 and 48 h and, in part, at 72 h. As anticipated, compound 2 was more potent than compound 1 at all time points. Conversely, in the IMR-32 cell line the antiproliferative activity was already evident at 24 h, whereas the additive effect of compounds 1 and 2 with respect to the parent compound Largazole was minimal or even absent.

To further explain the additive antiproliferative effect of compounds 1 and 2 vs Largazole, their metabolic stability was assessed with respect to Largazole in the assay cell medium. As expected, a rapid hydrolysis of the thioester moiety was observed (Table 2, Supporting Information). The chemical stability of these compounds was evaluated also in HEPES and DMSO, without observing chemical degradation, hence confirming the potential use of these compounds as prodrugs. Finally, the stability in human plasma profile was evaluated (Table 2, Supporting Information), detecting the same rapid hydrolysis of the metabolically labile thioester side chain reported in the literature for Largazole.38,39

Conclusions

Novel Largazole derivatives bearing one and two nitrate groups at the metabolically labile thioester side chain were efficiently synthesized. These compounds were endowed with dual activity profile, as a consequence of the rapid liberation in cell medium of the HDAC inhibitor Largazole-thiol and the efficient production of NO. When characterized in terms of cytotoxicity in three different types of tumor cell lines, namely, U-2OS, Caco-2, and IRM-32, compounds 1 and 2 showed an additive antiproliferative activity compared to the parent compound Largazole, an effect which was more pronounced in the U-2OS and Caco-2 cells than in IRM-32.

Additional antiproliferative studies are being performed in different types of cancer cell lines to further explore the anticancer potential of compounds 1 and 2. The relative results will be reported in due course.

Acknowledgments

The authors would like to thank Marco Lolli (Università degli studi di Torino) and Maria Frosini (Università degli Studi di Siena) for the characterization of compounds 1 and 2 in the in vitro NO release assay.

Glossary

Abbreviations

HDAC

histone deacetylase

HDACi

histone deacetylase inhibitor

MW

microwave reactor

NO

nitric oxide

cGMP

cyclic guanosine monophosphate

Trt

trityl

DIC

N,N′-diisopropylcarbodiimide

DCM

dichloromethane

DMAP

4-dimethylaminopyridine

DCE

1,2-dichloroethane

TFA

trifluoroacetic acid

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00643

  • Synthetic procedures, characterization of chemical intermediates and final compounds, and details of biological assay protocols (PDF)

Author Present Address

○ Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy.

Author Contributions

∇ M.B. and R.D.F. share senior authorship. All authors equally contributed to the preparation of this manuscript and gave approval to the final version.

This project was financially supported by the COLLEZIONE DEI COMPOSTI CHIMICI E CENTRO DI SCREENING–CNCCS scarl under the PRONAT research project framework.

The authors declare no competing financial interest.

Dedication

# This article is dedicated to the memory of Professor Maurizio Botta, deceased on August 2nd 2019, who spent his entire life in science aiming for improving the quality of the life of human beings.

Supplementary Material

ml9b00643_si_001.pdf (172.6KB, pdf)

References

  1. Taori K.; Paul V. J.; Luesch H. Structure and Activity of Largazole, a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca Sp. J. Am. Chem. Soc. 2008, 130, 1806–1807. 10.1021/ja7110064. [DOI] [PubMed] [Google Scholar]
  2. Yu M.; Salvador L. A.; Sy S. K. B.; Tang Y.; Singh R. S. P.; Chen Q.-Y.; Liu Y.; Hong J.; Derendorf H.; Luesch H. Largazole pharmacokinetics in rats by LC-MS/MS. Mar. Drugs 2014, 12, 1623–1640. 10.3390/md12031623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Hong J.; Luesch H. Largazole: From Discovey to Broad-Spectrum Therapy. Nat. Prod. Rep. 2012, 29, 449–456. 10.1039/c2np00066k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ying Y.; Taori K.; Kim H.; Hong J.; Luesch H. Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase Inhibitor. J. Am. Chem. Soc. 2008, 130, 8455–8459. 10.1021/ja8013727. [DOI] [PubMed] [Google Scholar]
  5. McClure J. J.; Li X.; Chou C. J. Advances and Challenges of HDAC Inhibitors in Cancer Therapeutics. Adv. Cancer Res. 2018, 138, 183–211. 10.1016/bs.acr.2018.02.006. [DOI] [PubMed] [Google Scholar]
  6. Choudhary C.; Kumar Gnad F.; Nielsen M. L.; Rehman M.; Walther T. C.; Olsen J. V.; Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009, 325, 834–840. 10.1126/science.1175371. [DOI] [PubMed] [Google Scholar]
  7. Dokmanovic M.; Clarke C.; Marks P. A. Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res. 2007, 5 (10), 981–989. 10.1158/1541-7786.MCR-07-0324. [DOI] [PubMed] [Google Scholar]
  8. Lombardi P. M.; Cole K. E.; Dowling D. P.; Christianson D. W. Structure, Mechanism, and Inhibition of Histone Deacetylases and Related Metalloenzymes. Curr. Opin. Struct. Biol. 2011, 21 (6), 735–743. 10.1016/j.sbi.2011.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Mrakovcic M.; Bohner L.; Hanisch M.; Fröhlich L. F. Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53. Int. J. Mol. Sci. 2018, 19 (12), 3952–3987. 10.3390/ijms19123952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Richon V. M. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br. J. Cancer 2006, 95 (Suppl 1), S2–S6. 10.1038/sj.bjc.6603463. [DOI] [Google Scholar]
  11. Hymes K. B. The role of histone deacetylase inhibitors in the treatment of patient with cutaneous T-cell lymphoma. Clin. Lymphoma Myeloma Leuk. 2010, 10, 98–109. 10.3816/CLML.2010.n.014. [DOI] [PubMed] [Google Scholar]
  12. Lee S. U.; Kwak H. B.; Pi S. H.; You S. K.; Byeon S. N.; Ying Y.; Luesch H.; Hong J.; Kim S. H. In Vitro and In Vivo Osteogenic Activity of Largazole. ACS Med. Chem. Lett. 2011, 2, 248–251. 10.1021/ml1002794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Liu Y.; Wang Z.; Wang J.; Lam W.; Kwong S.; Li F.; Friedman S. L.; Zhou S.; Ren Q.; Xu Z.; Wang X.; Ji L.; Tang S.; Zhang H.; Lui E. L.; Ye T. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling. Liver Int. 2013, 33 (4), 504–515. 10.1111/liv.12034. [DOI] [PubMed] [Google Scholar]
  14. Poli G.; Di Fabio R.; Ferrante L.; Summa V.; Botta M. Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships. ChemMedChem 2017, 12, 1917–1926. 10.1002/cmdc.201700563. [DOI] [PubMed] [Google Scholar]
  15. Bhansali P.; Hanigan C. L.; Casero R. A. Jr; Tillekeratne L. M. W. Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation. J. Med. Chem. 2011, 54, 7453–7463. 10.1021/jm200432a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bowers A. A.; West N.; Newkirk T. L.; Troutman-Youngman A. E.; Schreiber S. L.; Wiest O.; Bradner J. E.; Williams R. M. Synthesis and Histone Deacetylase Inhibitory Activity of Largazole Analogs: Alteration of the Zinc-Binding Domain and Macrocyclic Scaffold. Org. Lett. 2009, 11, 1301–1304. 10.1021/ol900078k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nakajima H.; Kim Y. B.; Terano H.; Yoshida M.; Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp. Cell Res. 1998, 241, 126–133. 10.1006/excr.1998.4027. [DOI] [PubMed] [Google Scholar]
  18. Li K. W.; Wu J.; Xing W.; Simon J. A. Total synthesis of the antitumor depsipeptide FR-901,228. J. Am. Chem. Soc. 1996, 118, 7237–7238. 10.1021/ja9613724. [DOI] [Google Scholar]
  19. Huerta S. Nitric Oxide for Cancer Therapy. Futur. Sci. OA 2015, 1 (1), FS044. 10.4155/fso.15.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Förstermann U.; Sessa W. C. Nitric oxide synthases: regulation and function. Eur. Heart J. 2012, 33 (7), 829–837. 10.1093/eurheartj/ehr304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Shefa U.; Yeo S. G.; Kim M. S.; Song I. O.; Jung J.; Jeong N. Y.; Huh Y. Role of Gasotransmitters in Oxidative Stresses, Neuroinflammation, and Neuronal Repair. BioMed Res. Int. 2017, 2017, 1–15. FSO44. 10.1155/2017/1689341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hirst D. G.; Robson T. Nitric oxide physiology and pathology. Methods Mol. Biol. 2011, 704, 1–13. 10.1007/978-1-61737-964-2_1. [DOI] [PubMed] [Google Scholar]
  23. Garthwaite J. Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci. 2008, 27, 2783–2802. 10.1111/j.1460-9568.2008.06285.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Choudhari S. K.; Chaudhary M.; Bagde S.; Gadbail A. R.; Joshi V. Nitric oxide and cancer: a review. World J. Surg. Oncol. 2013, 11, 118–128. 10.1186/1477-7819-11-118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ridnour L. A.; Thomas D. D.; Switzer C.; Wink D. A. Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 2008, 19, 73–76. 10.1016/j.niox.2008.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kashfi K.; Vannini F. Nitric Oxide and Cancer: To Inhibit or To Induce iNOS: That Is the Question?. Therapeutic Application of Nitric Oxide in Cancer and Inflammatory Disorders 2019, 93–111. Chapter 5 10.1016/B978-0-12-816545-4.00005-0. [DOI] [Google Scholar]
  27. Ding Q. G.; Zang J.; Gao S.; Gao Q.; Duan W.; Li X.; Xu W.; Zhang Y. Nitric Oxide Donor Hybrid Compounds as Promising Anticancer Agents. Drug Discoveries Ther. 2016, 10 (6), 276–284. 10.5582/ddt.2016.01067. [DOI] [PubMed] [Google Scholar]
  28. Nott A.; Watson P. M.; Robinson J. D.; Crepaldi L.; Riccio A. S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 2008, 455, 411–415. 10.1038/nature07238. [DOI] [PubMed] [Google Scholar]
  29. Illi B.; Dello Russo C.; Colussi C.; Rosati J.; Pallaoro M.; Spallotta F.; Rotili D.; Valente S.; Ragone G.; Martelli F.; Biglioli P.; Steinkuhler C.; Gallinari P.; Mai A.; Capogrossi M. C.; Gaetano C. Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling. Circ. Res. 2008, 102, 51–58. 10.1161/CIRCRESAHA.107.157305. [DOI] [PubMed] [Google Scholar]
  30. Borretto E.; Lazzarato L.; Spallotta F.; Cencioni C.; D’Alessandra Y.; Gaetano C.; Fruttero R.; Gasco A. Synthesis and Biological Evaluation of the First Example of NO-Donor Histone Deacetylase Inhibitor. ACS Med. Chem. Lett. 2013, 4 (10), 994–999. 10.1021/ml400289e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Serafim R. A. M.; Pernichelle F. G.; Ferreira E. I. The Latest Advances in the Discovery of Nitric Oxide Hybrid Drug Compounds. Expert Opin. Drug Discovery 2017, 12 (9), 941–953. 10.1080/17460441.2017.1344400. [DOI] [PubMed] [Google Scholar]
  32. Chegaev K.; Riganti C.; Lazzarato L.; Rolando B.; Guglielmo S.; Campia I.; Fruttero R.; Bosia A.; Gasco A. Nitric Oxide Donor Doxorubicins Accumulate into Doxorubicin-Resistant Human Colon Cancer Cells Inducing Cytotoxicity. ACS Med. Chem. Lett. 2011, 2 (7), 494–497. 10.1021/ml100302t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zhao J.; Gou S.; Sun Y.; Yin R.; Wang Z. Nitric Oxide Donor-Based Platinum Complexes as Potential Anticancer Agents. Chem. - Eur. J. 2012, 18 (45), 14276–14281. 10.1002/chem.201201605. [DOI] [PubMed] [Google Scholar]
  34. Fang L.; Wang M.; Gou S.; Liu X.; Zhang H.; Cao F. Combination of Amino Acid/Dipeptide with Nitric Oxide Donating Oleanolic Acid Derivatives as PepT1 Targeting Antitumor Prodrugs. J. Med. Chem. 2014, 57 (3), 1116–1120. 10.1021/jm401634d. [DOI] [PubMed] [Google Scholar]
  35. Duan W.; Li J.; Inks E. S.; Chou C. J.; Jia Y.; Chu X.; Li X.; Xu W.; Zhang Y. Design, Synthesis, and Antitumor Evaluation of Novel Histone Deacetylase Inhibitors Equipped with a Phenylsulfonylfuroxan Module as a Nitric Oxide Donor. J. Med. Chem. 2015, 58 (10), 4325–4338. 10.1021/acs.jmedchem.5b00317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. For the synthesis of Largazole see:; Chen Q.-Y.; Chaturvedi P. R.; Luesch H. Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor. Org. Process Res. Dev. 2018, 22, 190–199. and references herein enclosed. 10.1021/acs.oprd.7b00352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Bryan N. S.; Grisham M. B. Methods to Detect Nitric Oxide and its Metabolites in Biological Samples. Free Radical Biol. Med. 2007, 43 (5), 645–657. 10.1016/j.freeradbiomed.2007.04.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Benelkebir H.; Marie S.; Hayden A. L.; Lyle J.; Loadman P. M.; Crabb S. J.; Packham G.; Ganesan A. Total Synthesis of Largazole and Analogues: HDAC Inhibition, Antiproliferative Activity and Metabolic Stability. Bioorg. Med. Chem. 2011, 19 (12), 3650–3658. 10.1016/j.bmc.2011.02.024. [DOI] [PubMed] [Google Scholar]
  39. Liu Y.; Salvador L. A.; Byeon S.; Ying Y.; Kwan J. C.; Law B. K.; Hong J.; Leusch H. Anticolon cancer activity of Largazole, a marine-derived tunable histone deacetylase inhibitor. J. Pharmacol. Exp. Ther. 2010, 335 (2), 351–361. 10.1124/jpet.110.172387. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml9b00643_si_001.pdf (172.6KB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES