Asymmetric Total Syntheses of (−)-Jorumycin, (−)-Renieramycin G, 3-epi-Jorumycin, and 3-epi-Renieramycin G

Lane, Jonathan W.; Chen, Yu-Yin; Williams, Robert M.

doi:10.1021/ja0535918

Cited by 99 publications

(69 citation statements)

References 20 publications

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“…1 Recently, we reported the asymmetric total syntheses of (−)-jorumycin (1) and (−)-renieramycin G (2). 6 However, en route to 1 and 2, a serendipitous discovery afforded a method to efficiently and selectively access two related natural product analogues, 3-epijorumycin (3) and 3-epi-renieramycin G (4). Preliminary biological evaluation of 3-epijorumycin (3), in addition to relevant synthetic intermediates, revealed low micromolar growth inhibition profiles for all compounds tested in the context of two human cancer cell lines (HCT-116 and A549).…”

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confidence: 99%

Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G

Lane

Estevez²,

Mortara³

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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Analogues of the tetrahydroisoquinoline family of antitumor antibiotics, 3-epi-jorumycin (3) and 3-epi-renieramycin G (4) in addition to their respective parent natural products (−)-jorumycin (1) and (−)-renieramycin G (2) were evaluated against both human colon (HCT-116) and human lung (A549) cancer cell lines. (−)-Jorumycin (1) displayed potent growth inhibition with GI 50 values in the low nanomolar range (1.9-24.3 nM), while compounds 2-4 were found to be substantially less cytotoxic (GI 50 0.6-14.0 µM).The tetrahydroisoquinoline family of alkaloids includes potent cytotoxic agents that display a range of biological properties such as antitumor and antimicrobial activities. 1 (−)-Jorumycin (1) (Figure 1), a member of the family, was isolated from the mantle and mucus of the pacific nudibranch Jorunna funebris 2 and is closely related to the saframycins, members of the renieramycin family, and, most notably, Ecteinascidin 743 (Et-743, 5) which was demonstrated to be a highly promising, exceedingly potent antitumor agent currently in phase II/III clinical trials. 3 Consistent with other members in the group, (−)-jorumycin (1) has been shown to harbor potent biological activities. 2,4 Fontana and coworkers, in the context of their original isolation studies, have demonstrated that 1 possesses activity against NIH 3T3 tumor cells (100% of inhibition at 50 ng/mL) in addition to P388, A549, HT29, and MEL28 tumor cell lines (IC 50 12.5 ng/mL). 2 Furthermore, 1 was shown to inhibit the growth of various Gram-positive bacteria (eg. Bacillus subtilis, Staphylococcus aureus) at a concentration lower than 50 ng/mL. 2 Saito and co-workers, employing (−)-jorumycin (1) prepared semisynthetically from renieramycin M, have reported potent antiproliferative activity for 1 against HCT-116 (IC 50 0.57 nM), QG56 (IC 50 0.76 nM), and DU145 (IC 50 0.49 nM) cell lines. 4 (−)-Renieramycin G (2) (Figure 1) was isolated from the marine sponge Xestospongia caycedoi by Davidson in 1992. 5 Despite having an amide carbonyl residue at C-21, 2 was reported to retain cytotoxicity against human cancer cells with MIC values of 0.5 µg/mL and 1.0 µg/mL against KB and LoVo cell lines, respectively. 5 These results are surprising in light of the fact that virtually all biologically active members of this family of tetrahydroisoquinoline alkaloids possess a carbinolamine or cyano function at C-21 that permits the formation of a potent, electrophilic iminium ion species that has been implicated

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confidence: 99%

Antitumor activity of tetrahydroisoquinoline analogues 3-epi-jorumycin and 3-epi-renieramycin G

Lane

Estevez²,

Mortara³

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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“…Piers reported that (trimethylstannyl)copper(I) dimethylsulfide complex was relatively unreactive towards α,β-unsaturated carbonyl compounds. 9 When a more reactive species [Me 3 SnCuCN]Li 10 was used in place of Me 3 SnCu·SMe 2 for this reaction we observed that the yield was dramatically improved. When 5a was added to [Me 3 SnCuCN]Li in dry THF at −78 °C, compound 6 and the corresponding Z-isomer were produced in a nearly 1:1 ratio with no recovery of starting material.…”

Section: Resultsmentioning

confidence: 94%

“…The addition of compound 5a to solution of Bu 3 SnCu·SMe 2 or [Bu 3 SnCuCN] Li 9,10 in THF resulted in no reaction. When 5a was added to Me 3 SnCu·SMe 2 in THF, compound 6 was obtained in 23% yield with 40% recovery of 5a.…”

Section: Resultsmentioning

confidence: 99%

“…Separation of the two isomers by flash chromatography proved to be very difficult and synthetically intractable. When [Me 3 SnCuCN]Li was treated with EtOH prior to the addition of 5a, the product obtained was exclusively the desired E-isomer. The geometric configuration of the product was determined by the coupling constant between the α-olefinic proton and the tin atom ( 117 Sn, 119 Sn) of the Me 3 Sn group.…”

Section: Resultsmentioning

confidence: 99%

“…We also examined reaction conditions by using a hindered tert-butyl ester that would favor the γ-stannane-type regioisomer 7b. Compound 5b underwent conjugate addition of [Me 3 SnCuCN]Li to yield the γ-substituted stannane 9 in 53% yield (Scheme 3). As a preliminary demonstration of the utility of this species, compound 9 underwent Stille crosscoupling with o-iodonitrobenzene to produce the γ-aryl-γ,δ-unsaturated amino acid derivative 10 in which the two ester groups are differentiated.…”

Section: Resultsmentioning

confidence: 99%

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