Abstract:Alkaloids U 0600One-Pot Synthesis of Simple Alkaloids: 2,3-Polymethylene-4(3H)-quinazolinones, Luotonin A, Tryptanthrin, and Rutaecarpine. -A convenient procedure affords 18 2,3-polymethylene-4(3H)-quinazolinones (III) and the alkaloids luotonin A (V), rutaecarpine (VII), and tryptanthrin (IX) in good to excellent yields. -(JAHNG, K. C.; KIM, S. I.; KIM, D. H.; SEO, C. S.; SON, J.-K.; LEE, S. H.; LEE, E. S.; JAHNG*, Y.; Chem.
“…60 This synthetic path is shown in Figure 6, and the concept behind this proposed mechanism is similar to the ones suggested by the most relevant publications. 15,62,63 It is worth mentioning that, like in the case of indirubin (2), the reaction between anthranilic acid (7) and isatin ( 6) is a common synthetic method for the production of tryptanthrin (3), 65,66 with distinct reference to the biosynthesis of the alkaloid. 31 However, when an ACN solution of the proposed intermediates isatin (6) and anthranilic acid (7) was stirred for 72 h at 23 °C, none of the desirable alkaloids were formed, suggesting the necessity of an oxidative means in the reaction medium, an assumption that is also in accordance with bibliographic data.…”
Section: ■ Discussionmentioning
confidence: 99%
“…31 However, when an ACN solution of the proposed intermediates isatin (6) and anthranilic acid (7) was stirred for 72 h at 23 °C, none of the desirable alkaloids were formed, suggesting the necessity of an oxidative means in the reaction medium, an assumption that is also in accordance with bibliographic data. 60,65,66 The aforementioned synthetic schemes represent largely the assumed mechanisms for the transformation of indole ( 8) to the two alkaloids with the exact same reaction conditions. The hypothesis is slightly altered, involving the condensation of two molecules of the produced isatin (6).…”
Malassezia
furfur isolates from diseased skin
preferentially biosynthesize compounds which are among the most active
known aryl-hydrocarbon receptor (AhR) inducers, such as indirubin,
tryptanthrin, indolo[3,2-b]carbazole, and 6-formylindolo[3,2-b]carbazole. In our effort to study their production from Malassezia spp., we investigated the role of indole-3-carbaldehyde
(I3A), the most abundant metabolite of Malassezia when grown on tryptophan agar, as a possible starting material for
the biosynthesis of the alkaloids. Treatment of I3A with H2O2 and use of catalysts like diphenyldiselenide resulted
in the simultaneous one-step transformation of I3A to indirubin and
tryptanthrin in good yields. The same reaction was first applied on
simple indole and then on substituted indoles and indole-3-carbaldehydes,
leading to a series of mono- and bisubstituted indirubins and tryptanthrins
bearing halogens, alkyl, or carbomethoxy groups. Afterward, they were
evaluated for their AhR agonist activity in recombinant human and
mouse hepatoma cell lines containing a stably transfected AhR-response
luciferase reporter gene. Among them, 3,9-dibromotryptanthrin was
found to be equipotent to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an AhR agonist, and 3-bromotryptanthrin was 10-times
more potent than TCDD in the human HG2L7.5c1 cell line. In contrast,
3,9-dibromotryptanthrin and 3-bromotryptanthrin were ∼4000
and >10,000 times less potent than TCDD in the mouse H1L7.5c3 cell
line, respectively, demonstrating that they are species-specific AhR
agonists. Involvement of the AhR in the action of 3-bromotryptanthrin
was confirmed by the ability of the AhR antagonists CH223191 and SR1
to inhibit 3-bromotryptanthrin-dependent reporter gene induction in
human HG2L7.5c1 cells. In conclusion, I3A can be the starting material
used by Malassezia for the production of both indirubin
and tryptanthrin through an oxidation mechanism, and modification
of these compounds can produce some highly potent, efficacious and
species-selective AhR agonists.
“…60 This synthetic path is shown in Figure 6, and the concept behind this proposed mechanism is similar to the ones suggested by the most relevant publications. 15,62,63 It is worth mentioning that, like in the case of indirubin (2), the reaction between anthranilic acid (7) and isatin ( 6) is a common synthetic method for the production of tryptanthrin (3), 65,66 with distinct reference to the biosynthesis of the alkaloid. 31 However, when an ACN solution of the proposed intermediates isatin (6) and anthranilic acid (7) was stirred for 72 h at 23 °C, none of the desirable alkaloids were formed, suggesting the necessity of an oxidative means in the reaction medium, an assumption that is also in accordance with bibliographic data.…”
Section: ■ Discussionmentioning
confidence: 99%
“…31 However, when an ACN solution of the proposed intermediates isatin (6) and anthranilic acid (7) was stirred for 72 h at 23 °C, none of the desirable alkaloids were formed, suggesting the necessity of an oxidative means in the reaction medium, an assumption that is also in accordance with bibliographic data. 60,65,66 The aforementioned synthetic schemes represent largely the assumed mechanisms for the transformation of indole ( 8) to the two alkaloids with the exact same reaction conditions. The hypothesis is slightly altered, involving the condensation of two molecules of the produced isatin (6).…”
Malassezia
furfur isolates from diseased skin
preferentially biosynthesize compounds which are among the most active
known aryl-hydrocarbon receptor (AhR) inducers, such as indirubin,
tryptanthrin, indolo[3,2-b]carbazole, and 6-formylindolo[3,2-b]carbazole. In our effort to study their production from Malassezia spp., we investigated the role of indole-3-carbaldehyde
(I3A), the most abundant metabolite of Malassezia when grown on tryptophan agar, as a possible starting material for
the biosynthesis of the alkaloids. Treatment of I3A with H2O2 and use of catalysts like diphenyldiselenide resulted
in the simultaneous one-step transformation of I3A to indirubin and
tryptanthrin in good yields. The same reaction was first applied on
simple indole and then on substituted indoles and indole-3-carbaldehydes,
leading to a series of mono- and bisubstituted indirubins and tryptanthrins
bearing halogens, alkyl, or carbomethoxy groups. Afterward, they were
evaluated for their AhR agonist activity in recombinant human and
mouse hepatoma cell lines containing a stably transfected AhR-response
luciferase reporter gene. Among them, 3,9-dibromotryptanthrin was
found to be equipotent to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an AhR agonist, and 3-bromotryptanthrin was 10-times
more potent than TCDD in the human HG2L7.5c1 cell line. In contrast,
3,9-dibromotryptanthrin and 3-bromotryptanthrin were ∼4000
and >10,000 times less potent than TCDD in the mouse H1L7.5c3 cell
line, respectively, demonstrating that they are species-specific AhR
agonists. Involvement of the AhR in the action of 3-bromotryptanthrin
was confirmed by the ability of the AhR antagonists CH223191 and SR1
to inhibit 3-bromotryptanthrin-dependent reporter gene induction in
human HG2L7.5c1 cells. In conclusion, I3A can be the starting material
used by Malassezia for the production of both indirubin
and tryptanthrin through an oxidation mechanism, and modification
of these compounds can produce some highly potent, efficacious and
species-selective AhR agonists.
“…Luotonin A (chemical purity >99.8%, Figure 1) was synthesized according to a previously described protocol (Jahng et al, 2008). Pooled human liver microsomes and cDNA-expressed recombinant CYP 1A2, 2A6, 2C8, 2C9, 2D6, 3A4, and 2E1 were purchased from BD Gentest (Woburn, MA, USA).…”
Section: Chemicalsmentioning
confidence: 99%
“…Because of the potential pharmacological effects of luotonin A for novel anti-cancer therapies, methods for the synthesis of luotonin A analogues have been reported to optimize the binding affinity to DNA and to increase water solubility (Twin & Batey, 2004;Bowman et al, 2007;Nacro et al, 2007;Jahng et al, 2008). The aromatic E-ring of luotonin A is important for the binding activity to DNA, although luotonin A does not contain a hydroxyl group in the C16 position analogous to the critical 20-OH group in camptothecin.…”
1. The pharmacological activity of luotonin A varies, depending on the type of functional group and the site of derivatization. To understand the in vivo efficacy of luotonin A, the in vitro metabolism of luotonin A was investigated in human liver microsomes and recombinant cDNA-expressed cytochromeP450 (CYP). 2. Incubation of luotonin A with pooled human liver microsomes in the presence of NADPH-generating system resulted in the formation of four metabolites and the structures of each metabolite were tentatively characterized on the basis of electrospray tandem mass spectra. 3. The main metabolic pathway of luotonin A in human liver microsomes was hydroxylation, resulting in the generation of two mono-hydroxyl metabolites (M1 and M2) and two di-hydroxyl metabolites (M3 and M4). CYP1A2 was primarily involved in hydroxylation of the quinolone moiety (M1 and M3), while CYP3A4 was mainly responsible for hydroxylation of the quinazoline moiety of luotonin A (M2 and M4) in human liver microsomes.
“…Tryptanthrin has been synthesized through many different routes, all of which involved the condensation of an anthranilic acid derivative (e.g., benzo[d][1,3]oxazine-2,4-dione, commonly called isatoic anhydride) with an indole derivative (e.g., indole-2,3-dione (isatin) or 1,3-dihydro-2-indolone (oxindole)) ( Scheme 1 ): The reaction of isatin 2 (or an oxindole) with isatoic anhydride 3 is the most common route to tryptanthrin [ 27 , 29 ]. Other methods include the reaction of thionyl chloride with anthranilic acid to give an intermediate 3,2,1-benzoxathiazin-4-one-2-oxide 4 , which reacted further with isatin to afford tryptanthrin in high yield [ 30 ], the chlorination of isatin with phosphorus oxychloride (or phosphorus pentachloride) to give 2-chloro-3-indolone 5, which upon further reaction with anthranilamide (or anthranilic acid) produced tryptanthrin in very high yield [ 19 , 31 , 32 ], reaction of phosphorus oxychloride with excess of isatin [ 33 ], a 3-component reaction of isatin with 2-azidobenzoyl chloride 6 and tributylphosphine to give 1 in about 40 % yield via an intramolecular aza-Wittig reaction [ 34 ] and ozonolysis of indigo 7 to give 2 and 3, which then underwent condensation to give tryptanthrin 1 in low yield [ 35 ] ( Scheme 1 ). Scheme 1 Synthetic routes to tryptanthrin and its atom numbering.…”
Tryptanthrin is a potent natural alkaloid with good in vitro pharmacological properties. Herein, we report the synthesis of the compound via a new method involving the reduction of isatin with solid-state-supported sodium borohydride under microwave irradiation. The title compound has been tested for its analgesic and antiinflammatory activity. The results showed that tryptanthrin dose dependently inhibits oedema and pain formation in all the models used. The agent also exhibited significant higher effects in its anti-inflammatory and analgesic activities better than positive drugs (aspirin and indomethacin) being currently used in the treatment and in the management of acute and chronic forms of pain and inflammatory disorders. The inhibitory potential of the compound was investigated by molecular docking using the software AutoDock Vina. The docking results were used to better rationalize the action and prediction of the binding affinity of tryptanthrin. Density Functional Theory (DFT) calculations at the B3LYP/6-311þþG (2df, 2pd) level of theory showed that compared to ascorbic acid, tryptanthrin shows higher antioxidant activity which may be improved upon by functionalizing the aromatic core to enhance its solubility in polar solvents. The calculated electronic and thermodynamic properties obtained for tryptanthrin compete well with the standard ascorbic acid.
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