Alkaloids Derived from Tryptophan: Terpenoid Indole Alkaloids

Ramani, Shilpa; Patil, Nandadevi; Nimbalkar, Suhas; Jayabaskaran, Chelliah

doi:10.1007/978-3-642-22144-6_21

Cited by 12 publications

(5 citation statements)

References 101 publications

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“…Vincristine (VCR; Oncovin) and vinblastine (VBL; Velbe) are the two major vinca alkaloids most widely used in chemotherapy regimens for the treatment of a variety of solid tumors as well as Hodgkin’s disease and leukemia. These anti-cancer alkaloids inhibit cell proliferation by binding to microtubules, leading to mitotic block and apoptosis [ 2 ], and they contain a bis-indole nitrogen moiety derived from tryptophan in the TIA pathway [ 3 ]. The first critical step in the biosynthesis of TIAs is a reaction catalyzed by tryptophan decarboxylase (TDC), which is encoded by a single gene in C .…”

Section: Introductionmentioning

confidence: 99%

An Endophytic Fungus, Talaromyces radicus, Isolated from Catharanthus roseus, Produces Vincristine and Vinblastine, Which Induce Apoptotic Cell Death

2015

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Endophytic fungi isolated from Catharanthus roseus were screened for the production of vincristine and vinblastine. Twenty-two endophytic fungi isolated from various tissues of C. roseus were characterized taxonomically by sequence analysis of the internal transcribed spacer (ITS) region of rDNA and grouped into 10 genera: Alternaria, Aspergillus, Chaetomium, Colletotrichum, Dothideomycetes, Eutypella, Eutypa, Flavodon, Fusarium and Talaromyces. The antiproliferative activity of these fungi was assayed in HeLa cells using the MTT assay. The fungal isolates Eutypella sp—CrP14, obtained from stem tissues, and Talaromyces radicus—CrP20, obtained from leaf tissues, showed the strongest antiproliferative activity, with IC50 values of 13.5 μg/ml and 20 μg/ml, respectively. All 22 endophytic fungi were screened for the presence of the gene encoding tryptophan decarboxylase (TDC), the key enzyme in the terpenoid indole alkaloid biosynthetic pathway, though this gene could only be amplified from T. radicus—CrP20 (NCBI GenBank accession number KC920846). The production of vincristine and vinblastine by T. radicus—CrP20 was confirmed and optimized in nine different liquid media. Good yields of vincristine (670 μg/l) in modified M2 medium and of vinblastine (70 μg/l) in potato dextrose broth medium were obtained. The cytotoxic activity of partially purified fungal vincristine was evaluated in different human cancer cell lines, with HeLa cells showing maximum susceptibility. The apoptosis-inducing activity of vincristine derived from this fungus was established through cell cycle analysis, loss of mitochondrial membrane potential and DNA fragmentation patterns.

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Section: Introductionmentioning

confidence: 99%

An Endophytic Fungus, Talaromyces radicus, Isolated from Catharanthus roseus, Produces Vincristine and Vinblastine, Which Induce Apoptotic Cell Death

2015

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“…While the pathway presented here is dedicated to PHE‐ and TYR‐derived products, an intermediate chassis could be constructed for TRP‐derived products. TRP is a precursor for many alkaloids of commercial value (Ramani et al., 2013 ) as well as for various pigments (Huccetogullari et al ., 2019 ). Chorismate lies at the branching point between TRP synthesis and PHE/TYR synthesis.…”

Section: Resultsmentioning

confidence: 99%

Yarrowia lipolyticachassis strains engineered to produce aromatic amino acids via the shikimate pathway

Larroude

Nicaud

Rossignol

2020

Microbial Biotechnology

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Yarrowia lipolytica is widely used as a microbial producer of lipids and lipid derivatives. Here, we exploited this yeast's potential to generate aromatic amino acids by developing chassis strains optimized for the production of phenylalanine, tyrosine and tryptophan. We engineered the shikimate pathway to overexpress a combination of Y. lipolytica and heterologous feedback-insensitive enzyme variants. Our best chassis strain displayed high levels of de novo Ehrlich metabolite production (up to 0.14 g l À1 in minimal growth medium), which represented a 93fold increase compared to the wild-type strain (0.0015 g l À1 ). Production was further boosted to 0.48 g l À1 when glycerol, a low-cost carbon source, was used, concomitantly to high secretion of phenylalanine precursor (1 g l À1 ). Among these metabolites, 2-phenylethanol is of particular interest due to its rose-like flavour. We also established a production pathway for generating protodeoxyviolaceinic acid, a dye derived from tryptophan, in a chassis strain optimized for chorismate, the precursor of tryptophan. We have thus demonstrated that Y. lipolytica can serve as a platform for the sustainable de novo bioproduction of high-value aromatic compounds, and we have greatly improved our understanding of the potential feedback-based regulation of the shikimate pathway in this yeast.

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“…The synthesis of 2,2-bis (3,3′-indolyl) propionic acid ( 4 ) (85% yield) was achieved by a Friedel–Crafts condensation of indole and pyruvic acid [10]. As tryptophan is well known as a precursor for a wide range of pharmacologically important indole alkaloids [11,12], we employed a one-pot synthesis of deoxy-pseudellone C ( 2 ) by first coupling 4 with tryptophan methyl ester to yield 3 (38%) [9], followed by LiOH-mediated hydrolysis to yield the free acid 3a (85% yield), then DCC-initiated amide coupling of 3a with methylamine to yield deoxy-pseudellone C ( 3a ) (37% yield, albeit with racemization about the single chiral center), and finally, DDQ oxidation of 2 to yield pseudellone C ( 1 ) (50% yield) (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned above, tryptophan is the precursor for a wide range of pharmacologically important indole alkaloids [11,12]. Tryptophan-derived indole alkaloids have been receiving wide attention in drug discovery for their promising therapeutic potentials, represented by the powerful chemotherapy drugs vinblastine and vincristine [19,20,21] and the antipsychotic and antihypertensive drug reserpine [22,23,24].…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Pseudellone Analogs and Characterization as Novel T-type Calcium Channel Blockers

et al. 2018

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T-type calcium channel (CaV3.x) blockers are receiving increasing attention as potential therapeutics for the treatment of pathophysiological disorders and diseases, including absence epilepsy, Parkinson’s disease (PD), hypertension, cardiovascular diseases, cancers, and pain. However, few clinically approved CaV3.x blockers are available, and selective pharmacological tools are needed to further unravel the roles of individual CaV3.x subtypes. In this work, through an efficient synthetic route to the marine fungal product pseudellone C, we obtained bisindole alkaloid analogs of pseudellone C with a modified tryptophan moiety and identified two CaV3.2 (2, IC50 = 18.24 µM; 3, IC50 = 6.59 µM) and CaV3.3 (2, IC50 = 7.71 µM; 3, IC50 = 3.81 µM) selective blockers using a FLIPR cell-based assay measuring CaV3.x window currents. Further characterization by whole-cell patch-clamp revealed a preferential block of CaV3.1 activated current (2, IC50 = 5.60 µM; 3, IC50 = 9.91 µM), suggesting their state-dependent block is subtype specific.

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Alkaloids Derived from Tryptophan: Terpenoid Indole Alkaloids

Cited by 12 publications

References 101 publications

An Endophytic Fungus, Talaromyces radicus, Isolated from Catharanthus roseus, Produces Vincristine and Vinblastine, Which Induce Apoptotic Cell Death

An Endophytic Fungus, Talaromyces radicus, Isolated from Catharanthus roseus, Produces Vincristine and Vinblastine, Which Induce Apoptotic Cell Death

Yarrowia lipolyticachassis strains engineered to produce aromatic amino acids via the shikimate pathway

Synthesis of Pseudellone Analogs and Characterization as Novel T-type Calcium Channel Blockers

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