Dolastatins 24: synthesis of (–)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleuine tert-butyl ester

Pettit, George R.; Srirangam, Jayaram K.; Singh, Sheo B.; Williams, M. D.; Herald, Delbert L.; Barkóczy, Jozsef; Kantoci, Darko; Hogan, Fiona

doi:10.1039/p19960000859

Cited by 27 publications

(34 citation statements)

References 33 publications

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“…The tripeptide Dov-Val-Dil TFA salt (15) and Boc-Dap (12) were obtained via published methods. 32,33 PyBroP coupling of amine 1a to Boc-Dap (12) followed by Boc deprotection with TFA in DCM afforded compound 14 (Scheme 5). Further coupling resulted in des-Doe D-10 stilbene amide 16.…”

Section: Resultsmentioning

confidence: 99%

“…To a stirred mixture of amine 1a (51 mg, 0.17 mmol), N α -Boc-L-Dap 12 (52 mg, 0.18 mmol, 1.1 eq), 32,33 and PyBroP (87 mg, 0.19 mmol, 1.1 eq) at 0 EC under Ar was added DIPEA (65 µL, 0.37 mmol, 2.2 eq). The reaction mixture was stirred for 1.5 h at rt.…”

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -Boc-l-dap)-amido-mentioning

confidence: 99%

“…The solvents were removed in vacuo, and the TFA salt, obtained by Sephadex LH-20 column chromatography (solvent, MeOH), was placed in methanol (1 mL). Sodium methoxide (0.22 mg, 0.41 mmol, 1.8 eq) was added to the reaction mixture, and the white precipitate that formed was collected and reprecipitated from DCM-CH 3 To a stirred mixture of amine 1a (51 mg, 0.17 mmol), N α -Boc-L-Dap 12 (52 mg, 0.18 mmol, 1.1 eq), 32,33 and PyBroP (87 mg, 0.19 mmol, 1.1 eq) at 0 EC under Ar was added DIPEA (65 µL, 0.37 mmol, 2.2 eq). The reaction mixture was stirred for 1.5 h at rt.…”

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -L-tyr)-amido-z-stmentioning

confidence: 99%

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Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

et al. 2005

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Further structure-activity relationship (SAR) exploration of 3,4-methylenedioxy-5,4′-dimethoxy-3′-amino-Z-stilbene (1a) derivatives resulted in the efficient synthesis of tyrosine amide hydrochloride 9, two tyrosine amide phosphate prodrugs (3a and 6), and sodium aspartate amide 11. Two additional cancer cell growth inhibitors (14 and 16) were synthesized by employing peptide coupling between amine 1a and the Dap residue of dolastatin 10 (4a) to yield amide 14 followed by to yield peptide 16. The latter represents a combination of stilbene 1a with the des-Doe tetrapeptide unit of the powerful tubulin assembly inhibitor dolastatin 10. Peptide 16 was examined for potential binding to tubulin in the vinca and/or colchicine regions and found to perform primarily as a relative of dolastatin 10. Amide 14 had anticryptococcal and antibacterial activities.We recently completed syntheses of 3'-amino derivatives (1a-b, 1d-j) of combretastatin A-2 (2c) 1 , encouraged by the remarkable success of the potent cancer vascular targeting [2][3][4] that occurs with combretastatin A-4 phosphate prodrug (CA4P) 2h. [5][6][7][8][9][10] Subsequently, we undertook the synthesis and initial anticancer evaluation of two phosphate derivatives (3a,b) of tyrosine stilbene amide 1i. Attachment of the phosphate group at the 3'-phenol position has been investigated in detail in the combretastatin A and B series. 1,[11][12][13] In the present study we chose to use the 4"-hydroxyl group of tyrosine amide 1i for attachment of a phosphate group (3a) as well as obtaining a diphosphoryl derivative (3b) by phosphorylating tyrosine amide 1i at both the amine 14 and hydroxyl groups. A parallel important objective of this research involved employing a tetrapeptide segment of dolastatin 10 (4a) for bonding to the 3′-amino group (1b). Dolastatin 10 (D-10, 4a), isolated 15-17 from the Indian Ocean sea hare Dolabella auricularia, has continued to progress through preclinical 18 and clinical development as an impressive antineoplastic agent. [19][20][21][22] Dolastatin 10 (4a) and various synthetic derivatives also have specific antifungal activity against Cryptococcus neoformans. 23,24 Previous SAR studies have confirmed that D-10 (4a) inhibits microtubule assembly by binding to the β-tubulin subunit near the vinca site. SAR studies have shown the des-Doe tetrapeptide unit (4b, Dov-Val-Dil-Dap) to be necessary for potent anticancer * To whom correspondence should be addressed. bpettit@asu 25,26 We now also report synthesis of the amide representing coupling of amine 1a to Dov-Val-Dil-Dap (4b). Results and DiscussionOur synthesis of the tyrosine stilbene amide 1i 27 presented the opportunity to develop two additional phosphate prodrugs in the combretastatin series. Accordingly, the 4"-phenol and α-amino groups were phosphorylated in one step using dibenzyl phosphite (1i to 5) (Scheme 1). Debenzylation of the resulting phosphate diesters (5) was achieved using bromotrimethylsilane to afford the free acid (3b) which was subsequently converted to sod...

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Section: Resultsmentioning

confidence: 99%

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -Boc-l-dap)-amido-mentioning

confidence: 99%

Section: 4-methylenedioxy-54′-dimethoxy-3′-(n α -L-tyr)-amido-z-stmentioning

confidence: 99%

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Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

et al. 2005

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“…We report here on its spectrum of activity, the duration of its postantifungal effect (PAFE), and its effect on cryptococcal budding. Dolastatin 10 and auristatin PHE were synthesized as described previously (20,22,25,26) and were stored desiccated in the dark. Prior to each experiment, the peptides were reconstituted in a small volume of sterile dimethyl sulfoxide (DMSO) and were then diluted in growth medium to the appropriate concentration.…”

mentioning

confidence: 99%

“…1A), was originally isolated from the Indian Ocean sea hare (Dolabella auricularia) (18). The development of an efficient synthetic route for this peptide (20,22) facilitated investigation of its remarkable cytostatic and antineoplastic activities (23), as well as the synthesis of numerous antitumor-active structural modifications (21,22). Dolastatin 10 is undergoing phase I and II cancer clinical trials, and its mammalian tubulin-binding activity has been described in detail (for a review, see reference 24).…”

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In Vitro Activities and Postantifungal Effects of the Potent Dolastatin 10 Derivative Auristatin PHE

Woyke

Pettit

Winkelmann

et al. 2001

Antimicrob Agents Chemother

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The pentapeptide dolavaline-valine-dolaisoleuine-dolaproine-phenylalanine-methyl ester (auristatin PHE) is a derivative of the anticancer drug dolastatin 10 (dolavaline-valine-dolaisoleuine-dolaproine-dolaphenine). Broth microdilution assays with a wide variety of yeast and filamentous fungal species demonstrated the specificity of auristatin PHE for Cryptococcus neoformans and several species of Trichosporon. The duration of the postantifungal effect (PAFE) for C. neoformans was determined for exposure times ranging from 30 min to 2 h. For the derivative, a PAFE was detectable after 45 min of exposure. The effect plateaued after 1 h of exposure, with a PAFE of approximately 6.5 h at four or eight times the auristatin PHE MIC. In contrast, there was no measurable PAFE after 1 h of exposure to dolastatin 10. Human serum greatly prolonged the PAFE of auristatin PHE at eight times the MIC. Auristatin PHE arrested C. neoformans in the budding stage, possibly due to a tubulin-inhibitory action. Auristatin PHE has potential as a narrow-spectrum fungicidal agent and as a probe that can be used to study cryptococcal cell division.Over the past two decades, the occurrence of life-threatening fungal infections in immunocompromised patients such as cancer patients has drastically increased. Although Aspergillus and Candida spp. represent the most common causes of these infections, an emerging number of other organisms including Cryptococcus neoformans and species of Trichosporon have been implicated (14,30,32). Existing therapies include flucytosine and polyene and azole antifungals such as amphotericin B and fluconazole (28). However, these antifungals are limited by host toxicities (30) and the emergence of drug resistance (3,9,13,33). Thus, the development of new antifungal agents with potent fungicidal activities and new cellular targets is critical.Dolastatin 10 (dolavaline-valine-dolaisoleuine-dolaproinedolaphenine) (19), a unique linear peptide (Fig. 1A), was originally isolated from the Indian Ocean sea hare (Dolabella auricularia) (18). The development of an efficient synthetic route for this peptide (20, 22) facilitated investigation of its remarkable cytostatic and antineoplastic activities (23), as well as the synthesis of numerous antitumor-active structural modifications (21, 22). Dolastatin 10 is undergoing phase I and II cancer clinical trials, and its mammalian tubulin-binding activity has been described in detail (for a review, see reference 24). Briefly, the peptide inhibits mammalian tubulin polymerization and the associated GTP hydrolysis (1) and acts as a noncompetitive inhibitor of vincristine and vinblastine (2).Recently, the antifungal spectrum of dolastatin 10 was reported (27). Against a limited number of yeasts and filamentous fungi, the compound had selective activity against C. neoformans. Included in the previous report (27) was the structural modification dolavaline-valine-dolaisoleuine-dolaproine phenylalanine-methyl ester (auristatin PHE) (25, 26) (Fig. 1B), which, in addition to extremely...

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Kornprobst

2014

Encyclopedia of Marine Natural Products

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Dolastatins 24: synthesis of (–)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleuine tert-butyl ester

Cited by 27 publications

References 33 publications

Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

Antineoplastic Agents. 515. Synthesis of Human Cancer Cell Growth Inhibitors Derived from 3,4-Methylenedioxy-5,4‘-dimethoxy-3‘-amino-Z-stilbene

In Vitro Activities and Postantifungal Effects of the Potent Dolastatin 10 Derivative Auristatin PHE

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