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A Convergent Total Synthesis of the Potent Cephalostatin/ Ritterazine hybrid - 25-epi Ritterostatin GN1N Ananda Kumar Kanduluru, Prabal Banergee, John Albert Beutler, and Philip L. Fuchs J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401171q • Publication Date (Web): 30 Jul 2013 Downloaded from http://pubs.acs.org on August 1, 2013
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The Journal of Organic Chemistry
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A Convergent Total Synthesis of the Potent Cephalostatin/ Ritterazine hybrid 4 5
- 25-epi Ritterostatin GN1N 7
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Ananda Kumar Kanduluru*,† Prabal Banerjee,† John A Beutler,‡ and Philip L Fuchs*,† 10 1 12 †
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Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States and ‡Molecular Targets
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Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States 16 18
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[email protected];
[email protected] 19 20 21 2 23 24 25 26 27 28 29 30 31 32 3 35
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ABSTRACT: The convergent synthesis of 25-epi ritterostatin GN1N is described for the first 36 37
time, starting from hecogenin acetate (HA). Stereoselective dihydroxylation employing the chiral 40
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ligand (DHQ)2PHAL was used as the key step to introduce the C25 epi- stereocenter on the north 42
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1 segment. The title compound was obtained through a coupling reaction between the C3-keto43 45
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azide (cstat North 1) and North G. 46 47 48 49
INTRODUCTION 50 52
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Cephalostatin 1 (Cstat 1) was isolated by the Petitt group 54
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from the marine tubeworm
Cephalodiscus gilchristi, collected from the Indian Ocean. It is one of the most potent anticancer 5 56 57 58 59 60 ACS Paragon Plus Environment
The Journal of Organic Chemistry
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molecules reported in the NCI 60 cell line testing (Figure 1). 2 Much effort has been devoted to 5
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the cephalostatins3 and very recently a new enantioselective synthesis of this complex molecule 7
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has been published4. A number of congeners have been isolated from marine sources, including 10
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cephalostatins 2-195 and ritterazines A-Z.5 The antineoplastic mechanism of the trisdecacyclic 12
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pyrazines is only partly known and the functionality present in these trisdecacyclic steroidal 13 14
pyrazine bisspiroketals is quite different from that of other anticancer agents, likely indicating a 17
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new mechanism of action. 6 Beyond in vitro testing, cephalostatin 1 has been shown to be 19
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effective in several xenografts including melanoma, sarcoma, leukemia and in a human 20 21
mammary carcinoma model. 7-8 24
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Among the series of analogs tested at the NCI (Table 1), 25-epi ritterostatin GN1N 5 exhibited 26
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sub-nanomolar activity (mean GI50 0.48 nM, Table 1 & Figure 1),8 which is 30 fold more potent 29
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than ‘natural’ epimer 4. These compounds showed selectivity for CNS, leukemia, and renal 31
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cancer cell lines, with ovarian cancer lines relatively resistant.7-8 As noted previously, this pattern 32 3
of selectivity is shared with several less potent natural products, including OSW-1, 36
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schweinfurthins, and stelletins.7 Several empirical calculations and docking/modeling studies 38
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also supported this higher activity. 6 In order to move agents of the trisdecacyclic pyrazine class 39 41
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to the clinic, a more efficient route to the north 1 hemisphere was required. This issue is 43
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addressed herein via a complete synthesis of 25-epi ritterostatin GN1N in a convergent manner 45
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from the readily available hecogenin for both segments, leading to 245 mg of the hybrid 46 47
molecule. 9 In this synthesis, the north G segment could be readily obtained from hecogenin 50
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acetate (HA).3 51 52 53 54 5 56 57 58 59 60 ACS Paragon Plus Environment
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The Journal of Organic Chemistry
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Figure 1. IC50 values of Cstat analogs 32 34
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Table 1. Selected results from NCI-60 cell line testing (IC50 values in nM). 35 36 38
37 Compd
NSC#
Leukemia
Lung
Colon
CNS
Breast
Ovary
Melanoma
Renal
Prostate
HL-60
A-549
HT-29
SF-295
MCF-7
IGROV1
M-14
A-498
PC-3
363979
0.4
0.5
1.4
1000
7.2
720780
