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Comparative Study
. 2015 Dec 16;13(12):7419-32.
doi: 10.3390/md13127074.

Structure-Activity Relationship and in Vivo Anti-Tumor Evaluations of Dictyoceratin-A and -C, Hypoxia-Selective Growth Inhibitors from Marine Sponge

Yuji Sumii  1 , Naoyuki Kotoku  2 , Akinori Fukuda  3 , Takashi Kawachi  4 , Masayoshi Arai  5 , Motomasa Kobayashi  6
Affiliations
Comparative Study

Structure-Activity Relationship and in Vivo Anti-Tumor Evaluations of Dictyoceratin-A and -C, Hypoxia-Selective Growth Inhibitors from Marine Sponge

Yuji Sumii et al. Mar Drugs. .

Abstract

Oral dictyoceratin-C (1) and A (2), hypoxia-selective growth inhibitors, showed potent in vivo antitumor effects in mice subcutaneously inoculated with sarcoma S180 cells. Structurally modified analogs were synthesized to assess the structure-activity relationship of the natural compounds 1 and 2 isolated from a marine sponge. Biological evaluation of these analogs showed that the exo-olefin and hydroxyl and methyl ester moieties were important for the hypoxia-selective growth inhibitory activities of 1 and 2. Thus far, only substitution of the methyl ester with propargyl amide in 1 was found to be effective for the synthesis of probe molecules for target identification.

Keywords: analog synthesis; dictyoceratin-A; dictyoceratin-C; hypoxia-selective growth inhibitor; in vivo antitumor effect; marine sponge; structure-activity relationship.

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Figures

Figure 1
Figure 1
Chemical structures of (+)-dictyoceratin-C (1) and -A (2).
Figure 2
Figure 2
In vivo antitumor effect of dictyoceratin-C (1) and A (2). (a) Mean ± SD of tumor weight of each group. * p < 0.05; (b) Images of surged tumors after two weeks.
Figure 3
Figure 3
Modification of functional groups for structure-activity relationship (SAR).
Scheme 1
Scheme 1
Synthesis of aromatic ring-modified analogs. Reagents and conditions: (a) Ph3PCH3Br, KHMDS, THF, 94%; (b) SOCl2, octanol, 50 °C, 13%; (c) EDCI·HCl, HOBt, propargylamine, DMF, 58%; (d) MeI, K2CO3, DMF, quant.; (e) propargyl bromide, K2CO3, DMF, 8: 35%, 9: 13%; (f) n-nonyl bromide, K2CO3, DMF, 10: 21%, 11: 14%.
Scheme 2
Scheme 2
Synthesis of exo-methylene-modified analogs. Reagents and conditions: (a) H2, Pd-C, MeOH (12a: 51%, 12b: 47%); (b) RhCl3·H2O, EtOH, reflux, 61%.
Scheme 3
Scheme 3
Synthesis of 8-methyl group-modified analogs. Reagents and conditions: (a) NaBH4, CeCl3·7H2O, MeOH, 94%; (b) 80% TFA, THF, 50 °C, 16: 97%, 21: 93%; (c) SOCl2, MeOH, 50 °C, 17: 98%, 22: 87%; (d) Ph3PCH3Br, KHMDS, THF, 18: 39%, 23: 95%; (e) NaH, CS2, THF, rt, then MeI, 50 °C, 94%; (f) nBu3SnH, AIBN, toluene, 80 °C, 86%.
Figure 4
Figure 4
Growth inhibitory activity of dictyoceratin analogs against DU145 cells. * p < 0.05.
Figure 5
Figure 5
Growth inhibitory activity of dictyoceratin-C (1) and propargyl amide analog (6) against DU145 cells. * p < 0.05.
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