Total Synthesis of Cribrostatin IV:  Fine-Tuning the Character of an Amide Bond by Remote Control

Chan, Collin; Heid, Richard; Zheng, Shengping; Guo, Jinsong; Zhou, Bishan; Furuuchi, Takeshi; Danishefsky, Samuel J.

doi:10.1021/ja050203t

Cited by 93 publications

(53 citation statements)

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“…5,11 Moreover, although the notion has not yet been proven, the absence of such a structural feature would perhaps significantly compromise if not entirely subvert the capacity of amide-containing tetrahydroisoquinoline members to form covalent bonds with ds-DNA. The inability to form covalent drug-DNA adducts would certainly account for a significant portion of the approximate two to three orders of magnitude difference in cytotoxicity 1,10 between these two classes of substrates.…”

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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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“…The progression of J5 to cribrostatin IV was nontrivial but, in the end, proved to be manageable. 35 K. Phalarine. In studying and prioritizing various conceptions with respect to a projected total synthesis of phalarine, we came to favor one in which a tetrahydro -carboline (AB indole) is joined through two critical bonds to a 4,5-disubstituted indole (EF indole) (Scheme 16).…”

Section: Discussion: Snapshots In Recent Total Synthesismentioning

confidence: 99%

Pattern Recognition in Retrosynthetic Analysis: Snapshots in Total Synthesis

Wilson

Danishefsky

2007

J. Org. Chem.

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In this Perspective, the value of small molecule natural products (SMNPs) in the discovery of active biological agents is discussed. The usefulness of the natural products-based method of potential pharma discovery is much augmented by the capacities of chemical synthesis. The great advances in synthetic methodology allow for major editing of the natural product in the hopes of optimizing potency and therapeutic index. As a consequence of the enormous increase in the power of multistep chemical synthesis, one can now approach structures of previously impractical complexity. In constructing a plan for a multistep synthesis, two complementary thought styles are often encountered. One is the traditional and extremely powerful concept of prioritized strategic bond disconnections. The other, which we term “pattern recognition,” involves the identification of moieties within the target, which are associated with reliable chemistry, and can serve to facilitate progress to the target. Recognition of such targets may require substantial recasting of the target structure to connect it to well-established types of transformations. Some of our older ventures, where ideas about pattern recognition were first being fashioned and used productively, are revisited. In addition, we provide snapshots of recently achieved total syntheses of SMNPs of novel biological potential. These vignettes serve to harmonize insights occasioned by pattern recognition, in concert with transformations enabled by the enormous growth in the power of synthesis.

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“…In the total synthesis of cribrostatin VI, the Danishefsky group successfully employed DPPA to displace a benzyl alcohol in high yield and ee. 11 Another example was demonstrated in the synthesis of …”

Section: Introductionmentioning

confidence: 99%

Diphenylphosphoryl Azide (DPPA) - A Reagent with Manifold Applications

Liang¹

2008

Synlett

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This feature focuses on a reagent chosen by a postgraduate, highlighting the uses and preparation of the reagent in current research Diphenylphosphoryl Azide (DPPA) -A Reagent with Manifold Applications Compiled by Huan LiangHuan Liang was born in Tianjin, P. R. of China in 1980. He received his B.Sc. in Chemistry from Tianjin University in 2003. He is now pursuing his Ph.D. under the supervision of Prof. Marco Ciufolini, Canada Research Chair in Synthetic Organic Chemistry, at the University of British Columbia. His research mainly focuses on natural product synthesis for pharmaceutical application.

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Total Synthesis of Cribrostatin IV: Fine-Tuning the Character of an Amide Bond by Remote Control

Abstract: We report the enantioselective total synthesis of cribrostatin IV (1). Key features of this synthesis involve the convergent coupling of two highly functionalized homochiral components followed by a "lynchpin" Mannich cyclization to establish the pentacyclic core (cf. 19 --> 20).

Cited by 93 publications

References 30 publications

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

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

Pattern Recognition in Retrosynthetic Analysis: Snapshots in Total Synthesis

Diphenylphosphoryl Azide (DPPA) - A Reagent with Manifold Applications

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