Synthesis and biological activity of artificial analogs of mycalamide A

Fukui, Hideto; Tsuchiya, Yoshihiro; Fujita, Keiko; Nakagawa, T.; Koshino, Hiroyuki; Nakata, Tadashi

doi:10.1016/s0960-894x(97)00365-x

Cited by 31 publications

(16 citation statements)

References 28 publications

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“…The combined organic extracts were washed with aqueous HCl (2 M) and brine, then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , 5-25% Et 2 O in hexanes) to give methyl ether 49a (412 mg, 0.794 mmol, 76%) as a colourless oil which solidified on standing: mp 30 To a solution of ester 49a (415 mg, 0.800 mmol) in THF (5 ml) at Ϫ80 ЊC was added Red-Al  (400 µl, 1.1 M in THF, 0.44 mmol) dropwise over 5 min. The cooling bath was removed and the clear colourless reaction mixture allowed to warm to 0 ЊC over 30 min whereupon acetone (40 µl) was added and the mixture then poured onto ice cold aqueous NaOH (1 M, 1.9 ml).…”

Section: (1r5r6r8r10s)-5-(tert-butylcarbonyloxy)methyl-8-{(2s)-3-[(te...mentioning

confidence: 99%

Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

Kocieński

Narquizian

Raubo

et al. 2000

J. Chem. Soc., Perkin Trans. 1

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Section: (1r5r6r8r10s)-5-(tert-butylcarbonyloxy)methyl-8-{(2s)-3-[(te...mentioning

confidence: 99%

Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

Kocieński

Narquizian

Raubo

et al. 2000

J. Chem. Soc., Perkin Trans. 1

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“…In 1997 the Nakata group (Fukui et al 1997) synthesized a set of ten advanced analogues of mycalamide A (Scheme 18) in order to probe the minimum structural requirements of the left fragment for biological activity and to explore the possibility of replacing the right fragment with glucose derivatives. The cytotoxicity against HeLa cells and antiviral activity against herpes simplex type I (HSV-l) and varicella-zoster virus (VZV) were tested in vitro, along with 5-tluorouracil and acyclovir as standards.…”

Section: Advanced Synthetic Analogues Of Mycalamide Amentioning

confidence: 99%

The Pederin Family of Antitumor Agents: Structures, Synthesis and Biological Activity

Narquizian¹,

Kocieński²

2000

The Role of Natural Products in Drug Discovery

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“…The reduction of the double bond was achieved by NaBH 4 -NiCl 2 in MeOH (80%). 18 In summary, we have reported a convenient synthetic route for the preparation of a substituted 2-oxo-1aza [5.3.0]bicycloalkane based on RCM cyclization. This bicyclic lactam could be used as scaffold for the synthesis of a cyclopentapeptide containing the RGD sequence for targeted chemotherapy strategies.…”

mentioning

confidence: 99%

Stereoselective Synthesis of a Functionalized 2-Oxo-1-azabicyclo[5.3.0]alkane as a Potential Scaffold for Targeted Chemotherapy Strategies

Bracci¹,

Manzoni²,

Scolastico³

2003

Synthesis

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A stereoselective synthesis of functionalized 2-oxo-1-azabicyclo[5.3.0]alkane is presented. Key events of the synthetic sequence were the stereoselective propenylation of an N-acyliminium ion and a ring-closing metathesis reaction forming a 7-membered lactam.Many physiological processes including cell activation, migration, proliferation and differentiation require direct contact between cells and the extracellular matrix. These interactions are mediated through several different families of CAMs (cell adhesion molecules) including the selectins, the integrins, the cadherins and the immunoglobulins. In particular, integrins are a/b heterodimeric cell surface receptors which play a major role in cell-cell and cell-matrix adhesive interactions 1 and represent the best opportunity of targeting small-molecule antagonists for both therapeutic and diagnostic use in various key diseases. 2 Bicyclo[x.y.0]alkanes 1 have served as scaffolds for the synthesis of integrin antagonists. 3 In particular, we have found that the 2-oxo-1-azabicyclo[5.3.0]alkane (2) 4 when incorporated in a cyclic RGD (Arg-Gly-Asp) peptide appears to force the two pharmacophoric groups of Asp and Arg to adopt the correct disposition to interact with the receptors 5 ( Figure 1). Compound 3 has shown to be highly active and selective toward the a v b 3 integrin which are expressed on the surface of a variety of cell types and are implicated in many pathological processes, such as tumor metastasis, angiogenesis, and osteoporosis. 6 Therefore, 3 could be a potential antitumor drug, and is currently under study in various animal models.Since the a v b 3 integrin is overexpressed by many tumors, ST1646 could also be seen as a tumor-homing peptide and, as such, it could be used to improve the therapeutic index of other cancer chemotherapeutics 7 by selective cell targeting. Thus, our recent efforts have been directed toward the synthesis of functionalised bicyclo[5.3.0]alkane scaffolds bearing appropiate side-chains that can be used to conjugate the most frequently used anticancer drugs to the integrin binders. Although many reports on the synthesis of bicyclic lactams 8,9 can be found in the literature, only a few describe the preparation of azabicyclo[x.y.0]alkanes bearing functionalised side-chains. 10 In the course of our studies on peptide secondary structure mimics we have already synthesized a functionalised 7,5-fused bicyclic lactam using a Horner-Emmons based strategy. 11 However, the number of steps of this approach and the importance of these compounds forced us to investigate new synthetic routes. We now report a stereoselective synthesis based on ring closing metathesis (RCM) 9k of a 7,5-trans-fused bicyclic lactam with a suitably functionalised side-chain.The starting material for the synthesis was the known 4-allyl pyroglutamic ester 4 12 (Scheme 1) which, after protecting group manipulation, was converted to the corresponding alcohol 5 via ozonolysis followed by in situ NaBH 4 reduction (80% over 3 steps). Hydroxy group protection as the s...

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Synthesis and biological activity of artificial analogs of mycalamide A

Cited by 31 publications

References 28 publications

Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

The Pederin Family of Antitumor Agents: Structures, Synthesis and Biological Activity

Stereoselective Synthesis of a Functionalized 2-Oxo-1-azabicyclo[5.3.0]alkane as a Potential Scaffold for Targeted Chemotherapy Strategies

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