Structure of 3189-13-7
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A tunable synthesis of indigoids: targeting indirubin through temperature
Shriver, James A. ; Kaller, Kaylie S. ; Kinsey, Ally L. ; Wang, Katelyn R. ; Sterrenberg, Summer R. ; Van Vors, Madison K. , et al.
Abstract: The spontaneous conversion of 3-indoxyl to indigo was a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids.
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Purchased from AmBeed: 1006-94-6 ; 3420-02-8 ; 1670-82-2 ; 10075-50-0 ; 3189-13-7 ; 933-67-5 ; 17422-33-2 ; 17422-32-1 ; 4769-96-4 ; 271-63-6 ; 6146-52-7 ; 614-96-0 ; 15861-24-2 ; 479-41-4 ; 25235-85-2 ; 1670-81-1 ; 120-72-9 ; 1074-88-0 ; 84-40-2 ; 19201-53-7 ; 482-89-3
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Gardner, Eric ;
Abstract: The overall aim of my work was to expand the practical utility of prenyltransferase_x005f_x0002_based biocatalysis as a tool in organic synthesis, natural product diversification, and drug discovery efforts. Aromatic prenyltransferases (PTs) serve a key role in the biosynthesis of countless bioactive natural products (NPs), by catalyzing the transfer of a 5 carbon prenyl(dimethylallyl) moiety from an alkyl pyrophosphate “donor”onto an aromatic “acceptor”substrate via electrophilic aromatic substitution. Many PTs have been observed to have remarkably broad substrate scopes, capable of accepting allylic, benzylic, heterobenzylic, and diene containing alkyl donors and transferring them to a range of phenolic and indole_x005f_x0002_containing substrates. Having evolved to carry out highly regioselective and chemoselective alkylation in complex chemical environments, PTs represent a powerful untapped source of late-stage functionalization catalysts for both natural and synthetic drug diversification efforts. Chapter 1 introduces and highlights the significance of indole-containing NPs and the diverse spectrum of biological activity that arises from substituted indole scaffolds. A brief overview of known synthetic methods for indole functionalization is covered, focusing on the challenges associated with functionalizing the benzenoid portion of indole. Subsequently, indole-modifying enzymes are introduced, and the structure, function, and mechanism of indole PTs is described as a foundation to this dissertation work. Chapter 2 demonstrates the utility of PT-based natural product diversification, in which the cytotoxic prenylated tryptophan-containing cyclic dipeptide tryprostatin B (TPS_x005f_x0002_B) wassynthesized and chemoenzymatically alkylated using the promiscuous PT CdpNPT. Using a library of 66 synthetic alkyl-pyrophosphate donors, 24 unique donors were accepted by CdpNPT in the presence of TPS-B to generate novel NP analogs. 11 of these chemoenzymatically produced TPS-B analogs were isolated for structure elucidation via nuclear magnetic resonance (NMR) to reveal high selectivity for indole C6 alkylation. Cytotoxicity assays revealed that the TPS-B analogs produced in this work have a potency similar to their parent NPs. This work demonstrates that PT-based biocatalysts can be used for the late-stage diversification of NPs which provides direct access to NP analogs not accessible through current synthetic methods. Chapter 3 outlines the synthesis and utilization of a series of azaindole-substituted tryptophan analogs (Aza-Trp) to probe the compatibility of tryptophan-PTs with medicinally relevant indole isosteres. Synthetic tryptophan-mimetic substrates containing additional aromatic N atoms at the 2, 4, 5, 6, and 7 positions were prepared and screened as substrates for the indole C4-PT FgaPT2. These results identified 4-azatryprophan and 5-azatryptophan as previously unreported substrate classes for aromatic PTs. After structural elucidation of the prenylated products, we discovered FgaPT2 catalyzed N_x005f_x0002_prenylation of the 6-membered ring of these azaindole substrates to form a cationic N_x005f_x0002_prenylpyridinium products. Not only is this the first report of chemoenzymatic prenylation of azaindole substrates, but this work uncovered a previously undocumented PT-catalyzed reaction. Chapter 4 reports the synthesis and evaluation of azaindole-substituted tryptophan-proline cyclic dipeptides (Aza-CyWP) as substrates for aromatic PTs, with the goal of chemoenzymatically producing azaindole-containing analogs of this privileged NP core scaffold with enhanced aqueous solubility and altered bioactivity. We discovered that the indole-C2 PT which has the native function of TPS-B biosynthesis, FtmPT1, was capable of prenylating all 5 azaindole-containing substrates. However, these synthetic substrates were found to alter the regioselectivity of prenylation in an azaindole iso_x005f_x0002_dependent manner, resulting in a total of 7 fully characterized N1, C2, and C3 prenylated products. Additionally, the highly promiscuous PT utilized in Chapter 2, CdpNPT, was found to accept the 7-azaindole containing Aza-CyWP, to produce cyclized C3-reverse prenylated and N1 prenylated products. Using the common medicinal chemistry strategy of isosteric replacement, azaindole containing NP analogs were successfully generated using indole PTs. This work represents the first step toward the application of PT-based biocatalytic functionalization of synthetic heterocyclic scaffolds commonly utilized in structure-activity relationship studies.
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Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT
Gardner, Eric D. ; Dimas, Dustin A. ; Finneran, Matthew C. ; Brown, Sara M. ; Burgett, Anthony W. ; Singh, Shanteri
Abstract: Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization However, the inability to perform late-stage modification of the indole ring has limited the structure-activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20-50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.
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Keywords: biocatalysts ; chemoenzymatic synthesis ; late-stage functionalization ; prenyltransferase ; tryprostatin
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Purchased from AmBeed: 71989-31-6 ; 3189-13-7 ; 3945-69-5 ; 70-23-5 ; 556-82-1
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CAS No. : | 3189-13-7 |
Formula : | C9H9NO |
M.W : | 147.17 |
SMILES Code : | C1=C(C=C2C(=C1)C=C[NH]2)OC |
MDL No. : | MFCD00022780 |
InChI Key : | QJRWYBIKLXNYLF-UHFFFAOYSA-N |
Pubchem ID : | 76659 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 44.79 |
TPSA ? Topological Polar Surface Area: Calculated from | 25.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.71 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 2.02 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 2.18 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.23 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.53 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.93 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.56 |
Solubility | 0.401 mg/ml ; 0.00273 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.17 |
Solubility | 0.989 mg/ml ; 0.00672 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.39 |
Solubility | 0.06 mg/ml ; 0.000407 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -5.76 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.2 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Tags: 3189-13-7 synthesis path| 3189-13-7 SDS| 3189-13-7 COA| 3189-13-7 purity| 3189-13-7 application| 3189-13-7 NMR| 3189-13-7 COA| 3189-13-7 structure
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