, Tulearin Derivatives 3.3.1, p.27
, 415 mmol) and pyridine (1 mL) in chloroform (3 mL), was added TsCl (160 mg, 0.8 mmol) at 0 °C After 48 h of stirring, EA was added and the organic phase was washed with saturated NH 4 Cl, water and brine, dried over anhydrous MgSO 4 and evaporated. The residue was purified by VLC (petroleum ether/ethyl acetate, 1:1) to afford ditosyl 26, as a colorless oil, 52 mg (20%) and 9-monotosyl 27, a second colorless oil, pp.43-78
, 45 (s, 3H, H-38); 9-Ts: ? 7); 3-Ts: ? 127.5 s (C-32), NMR data for modified site (C3?C10): 1 H-NMR (CDCl 3 , 500 MHz) ? 4.50 (m, 1H 4.69 (m, 1H, H-9), 1.57 (m, 1H, H-10);. 3-Ts: ? 7.35 (d, 2H, H-33,34), 7.79 (d, 2H, H-35,36)); 13 C-NMR (CDCl 3 , 125 MHz) ? 80.4 d (C-3), 35.3 t, pp.78-127
, CHCl 3 ); NMR data for modified site (C8?C10): 1 H-NMR (CDCl 3 , 500 MHz) ? 4.78 (m, 1H, H-8), 4.69 (m, 1H, H-9), 1.57 (m, 1H, H-10); 9-monoTs: ? 7, pp.25-42
, 9-monoTs: ? 127.5 s (C-32), 129.9 d (C-33, 137.0 s (C-37), pp.0-38
,
, The mixture was stirred at room temperature for 24 h. DCM was then added (5 mL) and the mixture was washed with saturated NH 4 Cl, water and brine, dried over anhydrous MgSO 4 and evaporated. The residue was purified by VLC (petroleum ether/ethyl acetate, 1:1) to afford 28, as a colorless oil, 7.2 mg (40%) [?] D 25 +27 (c 0.2, CHCl 3 ); NMR data for modified site (C8?C10): 1 H-NMR (CDCl 3, DCM (2 mL) were added Et 3 N (5.2 mg J = 5.3 Hz, 1H, H-9), 1.62 (m, 2H, H-10); Aryl group (Ar): ? 7.90 Hz, H-36,37); 13 C-NMR (CDCl 3 , 125 MHz) ? 74.3 d (C-8), 73 Aryl group (Ar): ? 165.2 s (C-32), pp.31-35
, 7 mmol) was added to a cold solution (0 °C ) of tulearin A (140 mg, 0.26 mmol) in pyridine (0.14 mL) The mixture was stirred at rt for 3 h. Then, water was added and the mixture extracted with DCM, Mesyl chloride (80 mg
, :1) to afford 29, as a colorless oil, 110 mg (61%) CHCl 3 ); NMR data for modified site, VLC, vol.4, issue.500, p.1
, 08 (s, CH 3 -Ms), 5.21 (brd, J = 8.9 Hz05 (s, 3H, 6.3 mg (37%); 36a: [?] D 25 +20 (c 0.2, CHCl 3 ); NMR data for modified site: 1 H-NMR (CDCl 3 , 500 MHz) ? 3.59 (ddd CHCl 3 ); NMR data for modified site, Hz, 1H, H-3), 3.29 (td MHz) ? 62.3 d (C-3), 62.7 d (C-9); HR-ESIMS m, pp.25-26, 2000.
, 13 C-NMR (CDCl 3 , 125 MHz) ? 62.8 d (C-3), 60.1 d (C-9); HR-ESIMS m/z calculated for C 31 H 51 N 7 O 4 Na (M + Na + ) 608.3900, found 608.3904 CHCl 3 ); NMR data for modified site: 1 H-NMR (CDCl 3 , 500 MHz) ? 3.77 (ddd, pp.8132-8171, 1988.
,
, enabled a preliminary SAR study (see Supporting Information) In respect to this, the finding that salarin C is more potent than salarin A, which differs only in the oxazole ring, suggests that this heterocycle is essential for activity. However, salarins F and I, which contain the oxazole ring but differ in the macrolide functional groups, do not display inhibitory activity on cell viability and proliferation [4]. Hence, biological activity of salarin C may rely on other moieties in addition to the heterocycle, or a combination of several moieties In this article we report a preliminary biological evaluation of the above derivatives against human leukemic cell line K562. It was found that the 16,17-vinyl epoxide of salarin C contributes significantly to the K562 inhibition (e.g., 5?13). However, this conclusion is not straightforward, namely, when the 16,17-epoxide was replaced by a 16-hydroxy-17-butylamine (14), the inhibition of K562 cell viability rose to 90% (based on different cell behavior) It is suggested that the butylamine group contributes to the activity of salarin C in a different, not yet identified, mechanism. Furthermore, compound 16 is also relatively active and the most active of the hydroxyl amine derivatives Again, this may be the result of another mechanism, Conclusions Cell Viability The availability of the ten natural salarins (A?J) and the above synthesized derivatives, which differ in particular chemical moieties The N-desacetylation (e.g., 16) affects, but does not abrogate the activity and therefore was not found as crucial for it, pp.16-18
, see Supporting Information), i.e., the octanoate ester is not crucial for the activity. The more polar glycosylation products, compounds 24 and 25, showed similar activity to 21 This section demonstrates that structural changes in the natural product are moderately effective in improving the efficacy of the molecule in inhibiting the viability of leukemia cells As for the tulearin derivatives, no significant changes were found for most of the compounds. The only exceptions to this were compounds 28 (showing 70% inhibition for K562 cells in comparison to tulearin A with 55%?60% inhibition) and 35 (92% inhibition), the former carrying a leaving group at position 9 and the latter at position 3. It is difficult to know whether the change in activity results from the change in the functional groups or from the solubility. Inter alia, the mono-substituted derivatives were found to be more active than the di-substituted ones. For example, mono-acetate 31 was found to inhibit K562 cells, more than the di-acetate 32 (inhibition of 28% compared to 6%) (Table 1). Unexpectedly, the tri-acetate 33 was even more active (45% inhibition) The acetyl carbamate functionality was found to slightly increase the cytotoxicity and to inhibit K562 better than the mono-and di-acetate, Alcohol 21 showed excellent results with similar activity to the natural product (1 ?M inhibited viability of the K562 leukemia cells by more than 90% comparison to the tri-substituted acetate, the tri-hexanoyl 34 showed weaker inhibition
, References and Notes
, sp., Organic Letters, vol.10, issue.19, pp.4307-4309, 2008.
DOI : 10.1021/ol801750y
URL : https://hal.archives-ouvertes.fr/hal-01188151
, Salarin C, a new cytotoxic sponge-derived nitrogenous macrolide, Tetrahedron Letters, vol.49, issue.28, pp.4355-4358, 2008.
DOI : 10.1016/j.tetlet.2008.05.038
URL : https://hal.archives-ouvertes.fr/hal-01188155
, Salarins A and B and Tulearin A:?? New Cytotoxic Sponge-Derived Macrolides, Organic Letters, vol.10, issue.2, pp.153-156, 2008.
DOI : 10.1021/ol702221v
URL : https://hal.archives-ouvertes.fr/hal-01188152
, Tausalarin C: A New Bioactive Marine Sponge-Derived Nitrogenous Bismacrolide, Organic Letters, vol.11, issue.16, pp.3538-3541, 2009.
DOI : 10.1021/ol9011019
URL : https://hal.archives-ouvertes.fr/hal-01188143
, Tulearins A, B, and C; structures and absolute configurations, Tetrahedron Letters, vol.50, issue.27, pp.3820-3822, 2009.
DOI : 10.1016/j.tetlet.2009.04.028
URL : https://hal.archives-ouvertes.fr/hal-01188142
, Kashman, Y. Salarins D?J, seven new nitrogenous macrolides from the Madagascar sponge Fascaplysinopsis sp, Tetrahedron, vol.6, pp.4339-4345, 2010.
, Recent N-Atom Containing Compounds from Indo-Pacific Invertebrates, Marine Drugs, vol.60, issue.11, pp.2810-2836, 2010.
DOI : 10.1021/np9606411
URL : https://hal.archives-ouvertes.fr/hal-01188135
, Salarin C, a member of the salarin superfamily of marine compounds, is a potent inducer of apoptosis, Investigational New Drugs, vol.9, issue.6, pp.98-104, 2010.
DOI : 10.2174/156800909789271512
, ChemInform Abstract: ACTIVATED CARBOXYLATES FROM THE PHOTOOXYGENATION OF OXAZOLES. APPLICATION TO THE SYNTHESIS OF RECIFEIOLIDE, CURVULARIN, AND OTHER MACROLIDES, Chemischer Informationsdienst, vol.37, issue.12, pp.4059-4067, 1981.
DOI : 10.1016/S0040-4020(01)93281-8
, Route of triacylamine formation in the thermal conversion of 2,3,7-trioxa-5-azabicyclo[2.2.1]hept-5-enes investigated by nuclear magnetic resonance experiments, Journal of the Chemical Society, Perkin Transactions 2, vol.2, issue.7, pp.1085-1089, 1991.
DOI : 10.1039/p29910001085
, Synthesis and interconversion of the four isomeric 6-oxo-2,4-heptadienoic acids, The Journal of Organic Chemistry, vol.50, issue.4, pp.447-451, 1985.
DOI : 10.1021/jo00204a004
, Structure and stereochemistry of constanolactones A-G, lactonized cyclopropyl oxylipins from the red marine alga Constantinea simplex, The Journal of Organic Chemistry, vol.59, issue.24, pp.7227-7237, 1994.
DOI : 10.1021/jo00103a012
, The Stereochemistry of the Cleavage of Steroidal Epoxides by Ceric Ammonium Nitrate, Journal of Chemical Research, issue.3, pp.118-11910, 1998.
DOI : 10.1039/a707312g
, Regio- and stereoselective ring opening of vinyl epoxides with MgBr2, Tetrahedron Letters, vol.45, issue.31, pp.5969-5972, 2004.
DOI : 10.1016/j.tetlet.2004.06.043
, Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: Applications to synthesis of (RS)(R)-propranolols and (RS)(R)(S)-naftopidils, J. Org. Chem, vol.72, pp.3713-3722, 2007.
, Acetylsuccinamide is known as an acetylating reagent, in case of salarin A (2) it turns out, that the C6-N (6) is weaker and cleaves to provide the open macrocycle, p.15
, High-field FT NMR application of Mosher's method. The absolute configurations of marine terpenoids, Journal of the American Chemical Society, vol.113, issue.11, pp.4092-4096, 1991.
DOI : 10.1021/ja00011a006
, Expedient Syntheses of Antofine and Cryptopleurine via Intramolecular 1,3-Dipolar Cycloaddition, The Journal of Organic Chemistry, vol.72, issue.13, pp.4886-4891, 2007.
DOI : 10.1021/jo070668x
, This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license