Synthesis 2018; 50(16): 3114-3130
DOI: 10.1055/s-0037-1610006
short review
© Georg Thieme Verlag Stuttgart · New York

From Natural to Artificial Antitumor Lipidic Alkynylcarbinols: Asymmetric Synthesis, Enzymatic Resolution, and Refined SARs

Dymytrii Listunov
a  CNRS, LCC (Laboratoire de Chimie de Coordination), 205 Route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France   Email: valerie.maraval@lcc-toulouse.fr   Email: chauvin@lcc-toulouse.fr
b  Université de Toulouse, UPS, ICT-FR 2599, 31062 Toulouse Cedex 9, France
,
Etienne Joly
c  UMR CNRS 5089, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 Route de Narbonne, 31077 Toulouse Cedex 4, France
,
Pauline Rullière
d  UMR CNRS 5068, LSPCMIB, Université de Toulouse, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France   Email: genisson@chimie.ups-tlse.fr
,
Hafida Gaspard
d  UMR CNRS 5068, LSPCMIB, Université de Toulouse, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France   Email: genisson@chimie.ups-tlse.fr
,
Vania Bernardes-Génisson
a  CNRS, LCC (Laboratoire de Chimie de Coordination), 205 Route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France   Email: valerie.maraval@lcc-toulouse.fr   Email: chauvin@lcc-toulouse.fr
b  Université de Toulouse, UPS, ICT-FR 2599, 31062 Toulouse Cedex 9, France
,
Yves Génisson*
d  UMR CNRS 5068, LSPCMIB, Université de Toulouse, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France   Email: genisson@chimie.ups-tlse.fr
,
Valérie Maraval*
a  CNRS, LCC (Laboratoire de Chimie de Coordination), 205 Route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France   Email: valerie.maraval@lcc-toulouse.fr   Email: chauvin@lcc-toulouse.fr
b  Université de Toulouse, UPS, ICT-FR 2599, 31062 Toulouse Cedex 9, France
,
a  CNRS, LCC (Laboratoire de Chimie de Coordination), 205 Route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France   Email: valerie.maraval@lcc-toulouse.fr   Email: chauvin@lcc-toulouse.fr
b  Université de Toulouse, UPS, ICT-FR 2599, 31062 Toulouse Cedex 9, France
› Author Affiliations
The Toulouse IDEX ‘Transversalité’ program 2015 is acknowledged for funding (Fishing-sponge project). The CNRS and the French Embassy in Kyiv (Ukraine) are acknowledged for their early contribution to the fellowship of D.L. P.R. is grateful to the ARC foundation for cancer research for postdoctoral funding.
Further Information

Publication History

Received: 07 April 2018

Accepted: 10 April 2018

Publication Date:
20 July 2018 (online)


Abstract

Among acetylenic natural products, chiral lipidic alkynylcarbinol (LAC) metabolites, mostly extracted from marine sponges, have revealed a broad spectrum of biological activities, in particular, remarkable antitumor cytotoxicity. With reference to one of the simplest natural representatives, [(S)-eicos-(4E)-en-1-yn-3-ol], and a given cancer cell line (HCT116), combined extensive efforts in chemical synthesis (relying on the use of a large chemical toolbox) and biological analysis (in vitro tests), have provided systematic structure–activity relationships (SARs) where the initially selected four structural parameters appear as independent principal components: (i) and (ii) the sp/sp2 content and extent of the terminal and internal unsaturations adjacent to the carbinol center, (iii) the absolute configuration of the latter, (iv) the length of the n-aliphatic backbone. Two key criteria have also been established regarding the functional alkynylcarbinol pharmacophore: the alkynylcarbinol unit must be both secondary and terminal (i.e., substituted by a short ethynyl or ethenyl C2 group). This review is intended to provide a further illustration of the value of a simple rational approach for drug design, and to act as a benchmark for future optimization of LACs as antitumor agents.

1 Introduction

2 2C2-Unsaturated Pharmacophore Candidates

2.1 Alkenylalkynylcarbinols (AACs)

2.2 Dialkynylcarbinols (DACs or DACys)

2.3 Alkynylalkenylcarbinols (iso-AACs) and Dialkenylcarbinols (DACes)

2.4 Oxidation-Protected Dialkynylcarbinols and Dialkynylketones

2.5 Fluorophore-Labeled Lipidic Dialkynylcarbinols

3 C2/C3-Unsaturated Pharmacophore Candidates

3.1 Cyclopropylalkynylcarbinols (CACs)

3.2 Allenylalkynylcarbinols (AllACs)

4 C2/C4- and 3C2-Unsaturated Pharmacophore Candidates

4.1 Butadiynylalkynylcarbinols (BACs)

4.2 Trialkynylcarbinols (TACs)

5 Double-AC-Headed Pharmacophore Candidates

6 Screening on the Lipidic Chain Length

7 Conclusion

 
  • References

  • 1 Current address: Department of Pathology, Michigan University, 1500 E. Medical Center, Ann Arbor, MI 48109-5054, USA.
  • 2 Listunov D. Maraval V. Chauvin R. Génisson Y. Nat. Prod. Rep. 2015; 32: 49
  • 3 Gunasekera SP. Faircloth GT. J. Org. Chem. 1990; 55: 6223
  • 4 Hallock YF. Cardellina JH. Balaschak MS. Alexander MR. Prather TR. Shoemaker RH. Boyd MR. J. Nat. Prod. 1995; 58: 1801
  • 5 Fusetani N. Shiragaki T. Matsunaga S. Hashimoto K. Tetrahedron Lett. 1987; 28: 4313
    • 6a Higa T. Tanaka J. Kitamura A. Koyama T. Takahashi M. Uchida T. Pure Appl. Chem. 1994; 66: 2227
    • 6b Kobayashi M. Mahmud T. Tajima H. Wang WQ. Aoki S. Nakagawa S. Mayumi T. Kitagawa I. Chem. Pharm. Bull. 1996; 44: 720
  • 7 Seo Y. Cho KW. Rho JR. Shin J. Sim CJ. Tetrahedron 1998; 54: 447

    • See for examples:
    • 8a Isaacs S. Kashman Y. Loya S. Hizi A. Loya Y. Tetrahedron 1993; 49: 10435
    • 8b Kim DK. Lee MY. Lee DS. Lee JR. Lee BJ. Jung JH. Cancer Lett. 2002; 185: 95
    • 8c Hong SY. Kim SH. Rhee MH. Kim AR. Jung JH. Chun T. Yoo ES. Cho JY. Naunyn-Schmeideberg’s Arch. Pharmacol. 2003; 368: 448
    • 8d Lee HS. Lee JH. Won H. Park SK. Kim HM. Shin HJ. Park HS. Sim CJ. Kim HK. Lipids 2009; 44: 71
  • 9 Sharma A. Chattopadhyay S. Tetrahedron: Asymmetry 1998; 9: 2635
  • 10 Gung BW. Dickson HD. Seggerson S. Bluhm K. Synth. Commun. 2002; 32: 2733
  • 11 Garcia J. Lopez M. Romeu J. Tetrahedron: Asymmetry 1999; 10: 2617
  • 12 Li ZY. Wang M. Bian QH. Zheng B. Mao JY. Li SN. Liu SZ. Wang MA. Zhong JC. Guo HC. Chem. Eur. J. 2011; 17: 5782
  • 13 Trost BM. Weiss AH. Org. Lett. 2006; 8: 4461
    • 14a Curran DP. Sui B. J. Am. Chem. Soc. 2009; 131: 5411
    • 14b Sui B. Yeh EA. H. Vurran DP. J. Org. Chem. 2010; 75: 2942
    • 15a Frantz DE. Fassler R. Carreira EM. J. Am. Chem. Soc. 2000; 122: 1806
    • 15b Frantz DE. Fassler R. Tomooka CS. Carreira EM. Acc. Chem. Res. 2000; 33: 373
  • 16 Kirkhman JE. D. Courteny TD. L. Lee V. Baldwin JE. Tetrahedron 2005; 61: 7219
  • 17 Li M. Zou C. Duhayon C. Chauvin R. Tetrahedron Lett. 2006; 47: 1047
    • 18a Moore D. Pu L. Org. Lett. 2002; 4: 1855
    • 18b Gao G. Moore D. Xie RG. Pu L. Org. Lett. 2002; 4: 4143
    • 18c Pu L. Acc. Chem. Res. 2014; 47: 1523
  • 19 Trost BM. Weiss AH. Jacobi von Wangelin A. J. Am. Chem. Soc. 2006; 128: 8
  • 20 El Arfaoui D. Listunov D. Fabing I. Oukessou M. Frongia C. Lobjois V. Samson A. Ausseil F. Ben-Tama A. El Hadrami EM. Chauvin R. Génisson Y. ChemMedChem 2013; 8: 1779

    • For natural product isolation, see:
    • 21a Aoki S. Matsui K. Wei H. Murakami N. Kobayashi M. Tetrahedron 2002; 58: 5417
    • 21b For biological studies, see: Izumi M. Yogosawa S. Aoki S. Watanabe H. Kamiyama J. Takahara Y. Sowa Y. Kobayashi M. Hosoi H. Sugimoto T. Sakai T. Int. J. Oncol. 2006; 29: 169
    • 21c For synthetic studies, see: Dzhemileva LU. D’yakonov VA. Makarov AA. Andreev EN. Yunusbaeva MM. Dzhemilev UM. Org. Biomol. Chem. 2017; 15: 470
  • 22 Haack KJ. Hashiguchi S. Fujii A. Ikariya T. Noyori R. Angew. Chem. Int. Ed. 1997; 36: 285
    • 23a Matsumura K. Hashiguchi S. Ikariya T. Noyori R. J. Am. Chem. Soc. 1997; 119: 8738
    • 23b Noyori R. Kitamura M. Angew. Chem. Int. Ed. 1991; 30: 49
  • 24 Listunov D. Billot C. Joly E. Fabing I. Volovenko Y. Génisson Y. Maraval V. Chauvin R. Tetrahedron 2015; 71: 7920
  • 25 Dembitsky VM. Lipids 2006; 41: 883
  • 26 Kim JS. Lim YJ. Im KS. Jung JH. Shim CJ. Lee CO. Hong J. Lee H. J. Nat. Prod. 1999; 62: 554
  • 27 Takanashi E. Takada K. Hashimoto M. Itoh Y. Ise Y. Ohtsuka S. Okada S. Matsunaga S. Tetrahedron 2015; 71: 9564
  • 28 Nuzzo G. Ciavatta ML. Villani G. Manzo E. Zanfardino A. Varcamonti M. Gavagnin M. Tetrahedron 2012; 68: 754
    • 29a Shin JH. Seao YW. Cho KW. Rho JR. Paul VJ. Tetrahedron 1998; 54: 8711
    • 29b Shin J. See Y. Cho KW. Rho JR. Paul VJ. Tetrahedron 1998; 54: 14636
  • 30 Chill L. Miroz A. Kashman Y. J. Nat. Prod. 2000; 63: 523
  • 31 Zhou G.-X. Molinski TF. Mar. Drugs 2003; 1: 46
  • 32 Rullière P., Lizeaux F., Joly E., Gaspard H., Maraval V., Chauvin R., Génisson Y.; submitted for publication.

    • For dideoxypetrosynol A, see:
    • 33a Choi HJ. Bae SJ. Kim ND. Jung JH. Choi YH. Int. J. Mol. Med. 2004; 14: 1091
    • 33b For petrotetrayndiol, see: Choi HJ. Yee SB. Park SE. Im E. Jung JH. Chung HY. Kim ND. Cancer Lett. 2006; 232: 214
    • 33c For (3S)-eicos-(4E)-en-1-yn-3-ol, see: Zovko A. Viktorsson K. Haag P. Kovalerchick D. Farnegardh K. Alimonti A. Ilan M. Carmeli S. Lewensohn R. Mol. Cancer Ther. 2014; 13: 2941
    • 34a Nickel S. Serwa RA. Kaschani F. Ninck S. Zweerink S. Tate EW. Maiser M. Chem. Eur. J. 2015; 21: 10721
    • 34b Zovko A. Novak M. Hååg P. Kovalerchick D. Holmlund T. Färnegårdh K. Ilan M. Carmeli S. Lewensohn R. Viktorsson K. Oncotarget 2016; 7: 50258
  • 35 Listunov D. Mazères S. Volovenko Y. Joly E. Génisson Y. Maraval V. Chauvin R. Bioorg. Med. Chem. Lett. 2015; 25: 4652
  • 36 Sivakumar K. Xie F. Cash BM. Long S. Barnhill HN. Wang Q. Org. Lett. 2004; 6: 4603
  • 37 Greenspan P. Mayer EP. Fowler SD. J. Cell. Biol. 1985; 100: 965
  • 38 Gocze PM. Freeman DA. Cytometry 1994; 17: 151
  • 39 Epshtein AE. Dolglii IE. Limanov VE. Skvortsova EK. Nefedov OM. Izv. Akad. Nauk. SSSR Ser. Khim. 1978; 2: 500 ; Russ. Chem. Bull. 1978, 27, 438
  • 40 Hoffmann-Roder A. Krause N. Angew. Chem. Int. Ed. 2004; 43: 1196
    • 41a de Graaf W. Smits A. Boersma J. van Koten G. Hoestra WP. Tetrahedron 1988; 44: 6699
    • 41b Schlingmann G. Milne L. Pearce CJ. Borders DB. Greenstein M. Maise WM. Carter GT. J. Antibiot. 1995; 48: 375
    • 41c For a review see: Nicolaou KC. Dai WM. Angew. Chem. Int. Ed. 1991; 30: 1387
    • 41d Zhang Y. Wu Y. Org. Biomol. Chem. 2010; 10: 4744
    • 42a Jones BC. N. M. Silverton JV. Simons C. Megati S. Nishimura H. Maeda Y. Mitsuya H. Zemlicka J. J. Med. Chem. 1995; 38: 1397
    • 42b Megati S. Goren Z. Silverton JV. Orlina J. Nishimura H. Shirasaki T. Mitsuya H. Zemlicka J. J. Med. Chem. 1992; 35: 4098 ; Erratum: J. Med. Chem. 1993, 36, 634
  • 43 Luo H. Ma S. Eur. J. Org. Chem. 2013; 3041
  • 44 Listunov D., Joly E., Duhayon C., Saffon-Merceron N., Fabing I., Génisson Y., Maraval V., Chauvin R. ChemMedChem 2018, in press, DOI: 10.1002/cmdc.201800284.
  • 45 Listunov D. Maraval V. Saffon-Merceron N. Mallet-Ladeira S. Voitenko Z. Volovenko Y. Génisson Y. Chauvin R. French-Ukr. J. Chem. 2015; 3: 21
  • 46 Sharma A. Chattopadhyay S. J. Org. Chem. 1998; 63: 6128
  • 47 Huang X. Cao T. Han Y. Jiang X. Lin W. Zhang J. Ma S. Chem.Commun. 2015; 51: 6956
    • 48a Bohlmann F. Arndt C. Bornowski H. Kleine KM. Chem. Ber. 1961; 94: 958
    • 48b Bohlmann F. Niedballa U. Rode K.-M. Chem. Ber. 1966; 99: 3552
    • 48c Crosby DG. Aharonson N. Tetrahedron 1967; 23: 465
    • 48d Bentley RK. Thaller V. Chem. Commun. (London) 1967; 439
    • 48e Bentley RK. Bhattacharjee D. Jones ER. H. Thaller V. J. Chem. Soc. C 1969; 685
    • 48f Yates SG. England RE. J. Agric. Food Chem. 1982; 30: 317
  • 49 Kitagawa I. Yoshikawa M. Yoshihara M. Hayashi T. Taniyama T. Yakugaku Zasshi 1983; 103: 612
    • 50a Zidorn C. Johrer K. Ganzera M. Schubert B. Sigmund EM. Mader J. Greil R. Ellmerer EP. Stuppner H. J. Agric. Food Chem. 2005; 53: 2518
    • 50b Christensen LP. Recent Pat. Food Nutr. Agric. 2011; 3: 64

    • For reviews on the synthesis and biological activities of butadiyne- and polyyne-containing natural products, see ref. 23 and
    • 50c Shi Shun AL. K. Tykwinski RR. Angew. Chem. Int. Ed. 2006; 45: 1034
    • 50d Minto RE. Blacklock BJ. Prog. Lipid Res. 2008; 47: 233
    • 51a Matsugana H. Katano M. Yamamoto H. Fujito H. Mori M. Takata K. Chem. Pharm. Bull. 1990; 38: 3480
    • 51b Bernart MW. Cardellina JH. Balaschak MS. Alexander MR. Shoemaker RH. Boyd MR. J. Nat. Prod. 1996; 59: 748
    • 51c Young JF. Duthie SJ. Milne L. Christensen LP. Duthie GG. Bestwick CS. J. Agric. Food Chem. 2007; 55: 618
    • 51d Siddiq A. Dembitsky V. Anti-Cancer Agents Med. Chem. 2008; 8: 132
    • 51e Yan Z. Yang R. Jiang Y. Yang J. Zhao Q. Lu Y. Molecules 2011; 16: 5561
    • 51f Liang C. Ding Y. Kim JA. Yang SY. Boo H.-J. Kang H.-K. Nguyen MC. Kim YH. Bull. Korean Chem. Soc. 2011; 32: 3513
  • 52 Heydenreuter W. Kunold E. Sieber SA. Chem. Commun. 2015; 15784
    • 53a Zheng G. Lu W. Aisa HA. Cai J. Tetrahedron Lett. 1999; 40: 2181
    • 53b McLaughlin NP. Butler E. Evans P. Brunton NP. Koidis A. Rai DK. Tetrahedron 2010; 66: 9681
    • 53c Yang Y.-Q. Li S.-N. Zhong J.-C. Zhou Y. Zeng H.-Z. Duan H.-J. Bian Q.-H. Wang M. Tetrahedron: Asymmetry 2015; 26: 361
  • 54 Listunov D. Saffon-Merceron N. Joly E. Fabing I. Génisson Y. Maraval V. Chauvin R. Tetrahedron 2016; 72: 6697
  • 55 Matovic NJ. Hayes PY. Penman K. Lehmann RP. De Voss JJ. J. Org. Chem. 2011; 76: 4467
  • 56 Nicolai S. Sedigh-Zadeh R. Waser J. J. Org. Chem. 2013; 78: 3783
  • 57 Bourkhis M. Listunov D. Gaspard H. Joly E. Abderrahim R. Maraval V. Génisson Y. Chauvin R. French-Ukr. J. Chem. 2017; 5: 24
  • 58 Detty MR. Luss HR. Organometallics 1992; 11: 2157
  • 59 Fusetani N. Kato Y. Matsunaga S. Hashimoto K. Tetrahedron Lett. 1983; 24: 2771
    • 60a Wright AE. McConnell OJ. Kohmoto S. Lui MS. Thompson W. Snader KM. Tetrahedron Lett. 1987; 28: 1377
    • 60b Hitora Y. Takada K. Okada S. Ise Y. Matsunaga S. J. Nat. Prod. 2011; 74: 1262
    • 61a Gung BW. Omollo AO. Eur. J. Org. Chem. 2008; 4790
    • 61b Gung BW. C. R. Chim. 2009; 12: 489
    • 62a Braekman JC. Daloze D. Devijver C. Dubut D. van Soest RW. M. J. Nat. Prod. 2003; 66: 871
    • 62b Shirouzu T. Watari K. Ono M. Koizumi K. Saiki I. Tanaka C. van Soest RW. M. Miyamoto T. J. Nat. Prod. 2013; 76: 1337
  • 63 Mori K. Akasaka K. Matsunaga S. Tetrahedron 2014; 70: 392
  • 64 Listunov D. Fabing I. Saffon-Merceron N. Gaspard H. Volovenko Y. Maraval V. Chauvin R. Génisson Y. J. Org. Chem. 2015; 80: 5386
  • 65 Bourkhis M. Gaspard H. Rullière P. de Almeida DK. C. Listunov D. Joly E. Abderrahim R. de Mattos MC. de Oliveira MC. F. Maraval V. Chauvin R. Génisson Y. ChemMedChem 2018; 13: 1124
  • 66 Despite the occurrence of ambiguous definitions in the literature, the eudismic ratio increases with the relative potency of the eutomer, e.g., ER = IC50(distomer)/IC50(eutomer), as explicitly formulated in the following article: Talon S. De Luca A. De Bellis M. Desaphy J.-F. Lentini G. Scilimati A. Corbo F. Franchini C. Tortorella P. Jockusch H. Conte Camerino D. Br. J. Pharmacol. 2001; 134: 1523