Radical Center Research Articles

Study protocol for an International Prospective Observational Cohort Study for Optimal Bowel Resection Extent and Central Radicality for Colon Cancer (T-REX study).

This is a prospective observational cohort study aiming to include 4000 patients with stages I to III colon cancer treated at 35 specialist institutions in Japan, South Korea, Germany, Russia, Lithuania and Taiwan. The anatomical distribution of lymph nodes and feeding arteries are investigated using surgical specimens according to pre-specified categorizing methods using intraoperative anatomical markings. Primary analyses are performed to identify the general principles of metastatic lymph node distribution in terms of its relation to the location of the primary tumor and feeding arteries. Secondary analyses will be used to estimate prognostic outcomes according to bowel resection length and central radicality and will be used to evaluate the quality of resected surgical specimens. Through in-depth lymph node mapping, standardized criteria for the definite area of ‘regional’ lymph node resection in routine surgical procedures can be identified, which is expected to contribute to international standardization in colon cancer surgery (ClinicalTrials.gov NCT02938481).

EPR Spectral Studies of Manganese(I) Based Molecular Squares

Manganese(I) based molecular squares of type [Mn(CO)3Br(μ-L)]4 where L = pyrazine, 4,4′-bipyridine, trans-1,2-bis(4-pyridyl)ethylene were synthesized and studied in detail by EPR spectroscopy. The continuous wave electron paramagnetic resonance (CW EPR) spectrum of these compounds consists of a broad transition at g = 2.006 and 4.16 that corresponds to an interacting low spin Mn(II) center and a narrow transition at g = 2.004 that corresponds to a nitrogen center radical. These results are discussed in detail and the observation of these characteristic EPR spectral signals is attributed to a partial transfer of an electron from Mn(I) center to the nitrogenous ligand through MLCT.

Impact of electron beam treatment on copolymers of polylactide and poly(trimethylene carbonate) in an air atmosphere

AbstractThe effect of exposure of polylactide (PLA) and poly(trimethylene carbonate) (PTMC) statistical copolymers to ionizing radiation was studied by means of EPR spectroscopy. In addition, the influence of radiation‐induced processes on thermal properties, miscibility of the components, weight average molecular weight (Mw) and number average molecular weight (Mn) were investigated for doses in the range of 0–200 kGy. In copolymers containing PLA and PTMC components in a ratio of 30:70 and 70:30 PLA radicals identified in the homopolymer under cryogenic conditions were dominant. This showed that PTMC radical centers either recombine or are transferred to PLA along the macromolecules. The results obtained for the non‐irradiated and irradiated samples showed that the glass transition values measured by differential scanning calorimetry and calculated using the Fox equation were similar and indicated compatibility between the constituents of the tested copolymers and their miscibility. Mw and Mn changes measured by gel permeation chromatography were used to determine the radiation yield of scission G(S) and cross‐linking G(X). In the case of PLA and PLA‐rich copolymers, the difference between G(S) and G(X) with increasing dose increased, thus the chain scission predominated over cross‐linking. For PTMC rich copolymer, the effect was opposite.

Synthesis, structure, luminescent properties and catecholase activity of Zn(II) complex with N, O chelating agent

A mononuclear tetrahedral Zn(II) complex [Zn(L)2](1)[HL = 2-(benzylimino)methyl)phenol] with phenol based bi-dentate N,O donor ligand have been prepared. The compound is characterized by various spectroscopic tools and the structure of the complex is solved by single crystal X-ray diffractometer. The tetrahedral Zn(II) complex crystallized in monoclinic space group I2/awith a = 12.2908(3) (Å), b = 9.1041(2) (Å), c = 19.9812(7) and β = 96.1466(10)°.Cyclic voltametric study of the complex 1 gives an irreversible oxidation peak due to ligand based oxidation of the phenol moiety to the phenoxyl radical. This compound also shows a strong emission band at 455 nm. The reported Zn(II) complex exhibits catecholase activity in methanol solvent under aerobic condition.The Kcatvalue for 1 in methanol is 8.411 × 103 h−1. The conversion of 3,5-di-tert-butyl catechol (3,5 DTBC) to 3,5-di-tert-butyl quinone (3,5 DTBQ) is catalysed by mono nuclear Zn(II) complex and the reaction proceeds through the generation of ligand centered phenoxyl radical.

Visible Light-Enabled sp3 -C-H Functionalization with Chloro- and Bromoalkynes: Chemoselective Route to Vinylchlorides or Alkynes.

An unprecedented direct atom‐economic chemo‐ and regioselective hydroalkylation of chloroalkynes and an sp3‐C−H alkynylation of bromoalkynes was achieved. The reaction partners are unfunctionalized ethers, alcohols, amides, and even non‐activated hydrocarbons. We found that a household fluorescent bulb was able to excite a diaryl ketone, which then selectively abstracts a H‐atom from an sp3‐C−H bond. The product of a formal alkyne insertion into the sp3‐C−H bond was obtained with chloroalkynes, providing valuable vinyl chlorides. The photo‐organocatalytic hydrogen atom transfer strategy gives rise to a broad range of diversely functionalized olefins. When bromoalkynes are applied in the presence of a base, a chemoselectivity switch to an alkynylation is observed. This reaction can even be performed for the alkynylation of unactivated sp3‐C−H bonds, in this case with a preference of the more substituted carbon. Accompanying quantum chemical calculations indicate a vinyl radical intermediate with pronounced linear coordination of the carbon radical center, thus enabling the formation of both diastereoisomers after H‐atom abstraction, suggesting that the (Z)‐diastereoisomer is preferred, which supports the experimentally observed (E/Z)‐distribution.

Stabilization of the Triplet Biradical Intermediate of 5-Methylcytosine Enhances Cyclobutane Pyrimidine Dimer (CPD) Formation in DNA.

Cyclobutane pyrimidine dimer (CPD) is a photoproduct formed by two stacked pyrimidine bases through a cycloaddition reaction upon irradiation. Owing to its close association with skin cancer, the mechanism of CPD formation has been studied thoroughly. Among many aspects of CPD, its formation involving 5-methylcytosine (5mC) has been of special interest because the CPD yield is known to increase with C5-methylation of cytosine. In this work, high-level quantum mechanics/molecular mechanics (QM/MM) calculations are used to examine a previously experimentally detected pathway for CPD formation in hetero (thymine-cytosine and thymine-5mC) dipyrimidines, which is facilitated through intersystem crossing in thymine and formation of a triplet biradical intermediate. A DNA duplex model system containing a core sequence TmCG or TCG is used. The stabilization of a radical center in the biradical intermediate by the methyl group of 5mC can lead to increased CPD yield in TmCG compared with its non-methylated counterpart, TCG, thereby suggesting the existence of a new pathway of CPD formation enhanced by 5mC.

Insights on unimolecular and bimolecular reactivity patterns of pyridyl, pyridyl-N-oxide, and pyridinyl radicals through spin density

Spin density is very vital in understanding the thermodynamic stability of radicals, biradicals, etc. To obtain insights on reactivity aspects of radicals using it, we carried out theoretical investigations on the unimolecular and bimolecular reactions of pyridyl1a-c, pyridyl-N-oxide2a-c, and pyridinyl3a-cradical isomers. For all the radicals, we computed the CH bond dissociation energies (BDEs), isomerization reactions through the 1,2-H shift, unimolecular decomposition channels, and the bimolecular reactions with small molecules H2, H2O, CO, CO2, CH4, and CH3OH. Remarkably, spin density at the radical center or the transition state manifested the observed reactivity patterns.

Time- and reduction-dependent rise of photosystem II fluorescence during microseconds-long inductions in leaves.

Lettuce (Lactuca sativa) and benth (Nicotiana benthamiana) leaves were illuminated with 720nm background light to mix S-states and oxidize electron carriers. Green-filtered xenon flashes of different photon dose were applied and O2 evolution induced by a flash was measured. After light intensity gradient across the leaf was mathematically considered, the flash-induced PSII electron transport (= 4·O2 evolution) exponentially increased with the flash photon dose in any differential layer of the leaf optical density. This proved the absence of excitonic connectivity between PSII units. Time courses of flash light intensity and 680nm chlorophyll fluorescence emission were recorded. While with connected PSII the sigmoidal fluorescence rise has been explained by quenching of excitation in closed PSII by its open neighbors, in the absence of connectivity the sigmoidicity indicates gradual rise of the fluorescence yield of an individual closed PSII during the induction. Two phases were discerned: the specific fluorescence yield immediately increased from Fo to 1.8Fo in a PSII, whose reaction center became closed; fluorescence yield of the closed PSII was keeping time-dependent rise from 1.8Fo to about 3Fo, approaching the flash fluorescence yield Ff = 0.6Fm during 40μs. The time-dependent fluorescence rise was resolved from the quenching by 3Car triplets and related to protein conformational change. We suggest that QA reduction induces a conformational change, which by energetic or structural means closes the gate for excitation entrance into the central radical pair trap-efficiently when QB cannot accept the electron, but less efficiently when it can.

Functional Outcome and Complications following Ileal Neobladder Reconstruction in Male Patients without Tumor Recurrence. More than 35 Years of Experience from a Single Center.

There is a lack of data on true long-term functional outcome of orthotopic bladder substitution. The primary study objective was to report our 35-year clinical experience. Since October 1985, 259 male patients from a large single center radical cystectomy series with complete followup of more than 60 months (median 121, range 60-267) without recurrence, irradiation or undiversion that might have affected the functional outcome, were included. Median age at radical cystectomy and at survey was 63 (range 23-81) and 75 (range 43-92) years, respectively. Overall 87% of patients voided spontaneously and residual-free. This rate decreased with increasing age at the time of surgery (less than 50 years old 94%, 70 years old or older 82%). Overall day/nighttime continence rates were 90%/82%. These rates decreased with increasing age at the time of surgery from 100%/88% to 87%/80%. The overall pad-free rate was 71%/47%. Bicarbonate use decreased from 51% (5 years) to 19% (25 years). Patients with a followup of more than 20 years had the lowest rate of residual urine and clean intermittent catheterization (0.0%) as well as use of more than 1 pad at daytime/nighttime (6.3%/12.5%) and mucus obstruction (0.0%). Serum creatinine showed only the age related increase. The surgical complication rate was 27% and correlated inversely with functional results (chi-squared 11.227, p <0.005), even when the younger age at the time of surgery (younger than 60 years) was related to higher rates of surgical complications (chi-squared 6.80, p <0.05). The ileal neobladder represents an excellent long-term option for urinary diversion with an acceptable complication rate.

Cross-Electrophile Couplings of Activated and Sterically Hindered Halides and Alcohol Derivatives.

Transition metal catalyzed cross-electrophile coupling of alkyl electrophiles has evolved into a privileged strategy that permits the facile construction of valuable C(sp3)-C bonds. Numerous elegant Ni-catalyzed coupling methods, for example, arylation, allylation, acylation, and vinylation of primary and secondary alkyl halides have been developed. This prior work has provided important mechanistic insights into the selectivity and reactivity of the coupling partners, which are largely dictated by both the catalysts and the reactants. In spite of the advances made to date, a number of challenging issues remain, including (1) achieving stereoselective syntheses of C-C bonds that rely primarily on functionalized or activated alkyl precursors, (2) diversifying the electrophiles, and (3) gaining insights into the underlying reaction mechanisms.In this Account, we summarize a number of Ni- and Fe-catalyzed reductive C-C bond forming methods developed in our laboratory, which have allowed us to couple activated, sterically hindered tertiary alkyl and C(sp3)-O bond electrophiles and to access methylated and trifluoromethylated products, esters, C-glycosides, and quaternary carbon centers. We will begin with a brief discussion of Ni-catalyzed chemoselective construction of unactivated alkyl-alkyl bonds, with focus on the effects of ligands and reductants, along with leaving group-directed reactivities of alkyl halides, and the role they play in promoting the reductive coupling of activated electrophiles, including methyl, trifluoromethyl, and glycosyl electrophiles, and chloroformates. Matching the reactivities of these electrophiles with suitable coupling partners is considered essential for success; this is something that can be tuned by means of appropriate Ni catalysts. Second, we will detail how tuning the steric and electronic effects of nickel catalysts with labile pyridine-type ligands and additives (primarily MgCl2) permits effective creation of arylated all-carbon quaternary centers through the coupling of aryl halides with sterically encumbered tertiary alkyl halides. In contrast, the use of bulkier bipyridine and terpyridine ligands permits the incorporation of relative small-sized acyl and allyl groups into acylated and allylated all-carbon quaternary centers. Finally, we will show how the knowledge gained with halide electrophiles enabled us to develop methods that permit the coupling of tertiary alkyl oxalates with allyl, aryl, and vinyl electrophiles, wherein Barton C-O bond radical fragmentation is mediated by Zn and MgCl2 and promoted by Ni catalysts. The same protocol is applicable to the arylation of secondary alkyl oxalates derived from α-hydroxyl carbonyl substrates, which involves the formation of relatively stable α-carbonyl carbon centered radicals. Thus, this Account not only summarizes synthetic methods that allow formation of valuable C-C bonds using challenging electrophiles but also provides insight into the relationship between the structure and reactivity of the substrates and catalysts, as well as the effects of additives.

Silicon\u2013silicon \u03c0 single bond

A carbon–carbon double bond consists of a σ bond and a π bond. Recently, the concept of a π single bond, where a π bond is not accompanied by a σ bond, has been proposed in diradicals containing carbon and heteroatom radical centers. Here we report a closed-shell compound having a silicon–silicon π single bond. 1,2,2,3,4,4-Hexa-tert-butylbicyclo[1.1.0]tetrasilane has a silicon−silicon π single bond between the bridgehead silicon atoms. The X-ray crystallographic analysis shows that the silicon−silicon π single bond (2.853(1) Å) is far longer than the longest silicon−silicon bond so far reported. In spite of this unusually long bond length, the electrons of the 3p orbitals are paired, which is confirmed by measurement of electron paramagnetic resonance, and magnetic susceptibility and natural bond orbital analysis. The properties of the silicon−silicon π single bond are studied by UV/Vis and 29Si NMR spectroscopy, and theoretical calculations.

Improved evaluation of spin-polarization energy contributions using broken-symmetry calculations.

Spin-polarization effects may play an important role in free radicals and in the magnetic coupling between radical centers. Starting from restricted open-shell calculations, i.e., a closed-shell description of the non-magnetic core electrons, a low-order perturbation expansion identifies the spin-polarization contribution to the energy of mono-radicals and to singlet-triplet energy differences in diradicals. Broken-symmetry (BS) single-determinant calculations introduce only a fraction of spin-polarization effects, and in a biased manner, since BS determinants are not spin eigenfunctions. We propose a simple technique to correctly evaluate spin-polarization energies by taking into account the effect of spin-flip components on one-hole one-particle excited configurations. Spin-decontamination corrections are shown to play a non-negligible role in the BS evaluation of bond energies. The importance of spin decontamination is illustrated in cases for which spin polarization is the leading contribution to the singlet-triplet gap, which characterizes twisted conjugated double bonds and disjoint diradicals.

Stable Luminescent Radicals and Radical-Based LEDs with Doublet Emission

Radical-based light-emitting diodes are an innovative type of organic light-emitting diodes (OLEDs), which adopt luminescent radicals as emitters, aiming at improving the external quantum efficienc...

Experimental and theoretical insight into the extraction mechanism, kinetics, thermodynamics, complexation and radiolytic stability of novel calix crown ether in ionic liquid with Sr2+

A comparative evaluation was carried out for the extraction of Sr2+ using novel calix crown ether in molecular diluent and in ionic liquid. Though the trend in extraction profiles was found to be similar for both the systems, still, almost 5 times higher distribution ratio (D) values were observed in ionic liquid. The speciation studies revealed that; neutral Sr (NO3)2. DHCC species was formed in dodecane and the extraction followed through ‘solvation’ mechanism. However, ionic liquid medium (IL), anionic species, [Sr(NO3)3. DHCC]− was found to be predominating indicating ‘anion exchange’ mechanism. The slower kinetics of extraction in IL was attributed to the high viscosity of IL. The extraction process was found to be spontaneous, endothermic and entropy driven.IL based system was found to be radiolytically more stable compared to the molecular diluent (Mol dil) based system. The electron paramagnetic resonance (EPR) spectroscopic investigation revealed the formation of oxygen centered radical with orthorhombic symmetry (gx = 2.00105, gy = 2.00475, gz = 2.00835) in irradiated ligand. The density functional theoretical (DFT) calculation was utilized to investigate the complexation and speciation in detail in microscopic level.

Radiative and Nonradiative Recombinations in Organic Radical Emitters: The Effect of Guest–Host Interactions

AbstractRadical‐carrying organic molecules have received significant attention to bypass the issue related to harvesting triplet excitons in current light‐emitting materials. While the computational efforts conducted so far have treated these radical emitters as isolated entities, in actual devices, they are embedded in a host matrix and subject to emitter–host interactions. Here, by combining molecular dynamics simulations and density functional theory calculations, the impact of the host matrix on the optoelectronic performance of radical emitters is evaluated, taking as a representative example the (4‐ncarbazolyl‐2,6‐dichlorophenyl)bis(2,4,6‐trichlorophenyl)‐methyl (TTM‐3NCz) radical emitter dispersed in a 4,4‐bis(carbazol‐9‐yl)biphenyl (CBP) host. A morphological analysis shows that steric effects around the radical centers, carried by the TTM electron‐poor moieties of the emitters, disfavor π–π interactions with the host molecules, which leads to random intermolecular orientations around the TTM moieties. The 3NCz electron‐rich moieties of the emitters, however, have much lesser spatial hindrance for intermolecular π–π stacking, which modulates the structural and electronic properties of the emitters in the host matrix. The influence of dynamic and static disorders on the radiative and nonradiative recombination processes is also investigated and it is found that the rates of nonradiative recombination are small, which opens the way to 100% internal quantum efficiency for the doublet‐based emission process.

Thiyl Radicals: Versatile Reactive Intermediates for Cyclization of Unsaturated Substrates.

Sulfur centered radicals are widely employed in chemical synthesis, in particular for alkene and alkyne hydrothiolation towards thioether bioconjugates. The steadfast radical chain process that enables efficient hydrothiolation has been explored in the context of cascade reactions to furnish complex molecular architectures. The use of thiyl radicals offers a much cheaper and less toxic alternative to the archetypal organotin-based radical methods. This review outlines the development of thiyl radicals as reactive intermediates for initiating carbocyclization cascades. Key developments in cascade cyclization methodology are presented and applications for natural product synthesis are discussed. The review provides a chronological account of the field, beginning in the early seventies up to very recent examples; a span of almost 50 years.

Tuning the active sites in reduced graphene oxide by hydroquinone functionalization for the aerobic oxidations of thiophenol and indane

Sustainable reduced graphene oxide (rGO) carbocatalysts for molecular oxygen activation have been developed based on the concept that chemical reduction of graphene oxide to rGO introduces functional groups that can become active sites. Thus, a series of rGOs prepared using hydroquinone (HQ), hydrazine (HZ) and ascorbic acid (ASC) as reducing agents have been tested as catalysts in the aerobic oxidations of thiophenol and indane. In both oxidation reactions, rGO reduced by HQ (rGO-HQ) exhibited the highest catalytic activity and stability. A high selectivity of ol/one (90 %) at around 30 % indane conversion in the absence of transition metals was achieved. Reusability test showed that the activity of rGO-HQ is mostly retained in three consecutive runs. Quenching experiments indicated that the reaction proceeds with the generation of hydroxyl and carbon centered radicals. The higher activity of rGO-HQ was attributed to the covalent anchoring of some HQ molecules on rGO during the chemical reduction. This knowledge has been used to develop a HQ-functionalized Merrifield resin that in spite of its very different textural properties compared to rGO also exhibits catalytic activity for O2 activation. The present work illustrates the potential to develop rGO carbocatalysts with an increased density of active sites by selecting an appropriate reducing agent during the chemical reduction of graphene oxide.

Intermixed medullary and papillary thyroid cancer in a patient with renal cell carcinoma.

SummaryWe report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN) metastases in a patient who was subsequently diagnosed with clear cell renal cell carcinoma (RCC). A 56 year old female presented with dysphagia and was found to have a left thyroid nodule and left superior cervical LN with suspicious sonographic features. Fine needle aspiration biopsy (FNAB) demonstrated PTC in the left thyroid nodule and MTC in the left cervical LN. Histopathology demonstrated multifocal PTC with 3/21 LNs positive for metastatic PTC. One LN in the left lateral neck dissection exhibited features of both MTC and PTC within the same node. In the right lobe, a 0.3 cm focus of MTC with extra-thyroidal extension was noted. Given persistent calcitonin elevation, a follow-up ultrasound displayed an abnormal left level 4 LN. FNAB showed features of both PTC and MTC on the cytopathology itself. The patient underwent repeat central and left radical neck dissection with 3/6 LNs positive for PTC in the central neck and 2/6 LNs positive for intermixed PTC and MTC in the left neck. There was no evidence of distant metastases on computed tomography and whole body scintigraphy, however a 1.9 x 2.5 cm enhancing mass within the right inter-polar kidney was discovered. This lesion was highly suspicious for RCC. Surgical pathology revealed a 2.5 cm clear cell RCC, Fuhrman grade 2/4, with negative surgical margins. She continues to be observed with stable imaging of her triple malignancies.Learning points:Mixed medullary-papillary thyroid neoplasm is characterized by the presence of morphological and immunohistochemical features of both medullary and papillary thyroid cancers within the same lesion. Simultaneous occurrence of these carcinomas has been previously reported, but a mixed disease within the same lymph node is an infrequent phenomenon.Prognosis of mixed medullary-papillary thyroid carcinomas is determined by the medullary component. Therefore, when PTC and MTC occur concurrently, the priority should be given to the management of MTC, which involves total thyroidectomy and central lymph node dissection.Patients with thyroid cancer, predominantly PTC, have shown higher than expected rates of RCC. To our knowledge, this is the first report describing the combination of MTC, PTC, and RCC in a single patient.

Oxidation kinetics of n-pentanol: A theoretical study of the reactivity of the 1‑hydroxy‑1-peroxypentyl radical

n-Pentanol has been considered as a promising alternative fuel for compression-ignition engines due to its potential to reduce greenhouse gases and pollutant emissions. Engine performance is strongly dominated by fuel oxidation chemistry, and thus a more accurate determination of the coefficients of the reactions ruling its oxidation is essential for the utilization of n-pentanol in combustion engines. The reactions involving 1‑hydroxy‑1-pentyl and molecular oxygen were found to play an important role in controlling the low temperature oxidation chemistry, but have not been investigated experimentally or theoretically; this is also the case for the reactions of the 1‑hydroxy‑1-peroxypentyl radical, which is formed by the addition of oxygen to the radical center of 1‑hydroxy‑1-pentyl. This work presents a theoretical study with high level ab initio calculations at the CCSD(T)/aug-cc-pVTZ//M06-2X/cc-pVTZ level of theory to shed light on the fate of the 1‑hydroxy‑1-peroxypentyl radical. The rate coefficients of all the possible intra-molecular hydrogen shift reactions of that radical were computed using variational transition state theory with small curvature tunneling corrections. For certain reactions, tunneling and variational effects are very pronounced, proving the need for robust methodologies to account for these effects. The hydrogen shift reaction leading to a concerted HO2 elimination and formation of n-pentanal is the dominant pathway and governs the reactivity of 1‑hydroxy‑1-peroxypentyl radical at any temperature. The reverse of this reaction was thereby investigated as well. For this prominent pathway, the effects of multistructural (multiple conformers) torsional anharmonicity of the stationary points were taken into account in order to refine the forward and reverse rate coefficients. The rate coefficients calculated at room temperature are compared to those calculated using a previously developed cost-effective multi-conformer transition state theory approach. The system-specific quantum Rice-Ramsperger-Kassel (SS-QRRK) theory was used to compute the pressure-dependent rate coefficients, which indicate significant pressure dependence at intermediate and high temperatures. Implementation of the calculated reaction rate coefficients in chemical kinetics models of n-pentanol revealed that our computed rate coefficients enable better insights into the chemistry of n-pentanol, and help to understand how n-pentanal is formed.

Tryptophan, a non-canonical melanin precursor: New L-tryptophan based melanin production by Rubrivivax benzoatilyticus JA2

Melanins are chemically diverse ubiquitous pigments found across the life forms synthesized via different biochemical pathways mainly from L-tyrosine or acetyl CoA. Though few reports suggest the possibility of tryptophan-based melanin synthesis, however, such tryptophan-based melanin and its biosynthesis remained a biochemical riddle. Here we report tryptophan-based melanin production by bacterium, Rubrivivax benzoatilyticus JA2. Aerobic cultures of strain JA2 produced brown pigment when grown on L-tryptophan-containing media. Purified pigment showed typical physico-chemical properties of melanin. Further, extensive spectroscopic studies revealed that pigment is an amorphous, indole-type polymer with stable free radical centers. Further, hydrolysis of the brown pigment revealed the presence of indole moiety, confirming the indolic nature of the pigment. Demonstration of in vitro and in vivo pigment synthesis directly from L-tryptophan or hydroxytryptophan confirms tryptophan-based melanin synthesis in strain JA2. Interestingly, canonical melanin biosynthetic inhibitors did not affect the pigment synthesis indicating possible non-canonical tryptophan-based melanin biosynthesis in strain JA2. Further, the exometabolite profiling and precursor feeding studies suggests that L-tryptophan converted to hydroxytryptophan/hydroxyindoles and their subsequent polymerization lead to the formation of melanin. The current study sheds light on biosynthetic diversity of melanins and L-tryptophan can be a potential precursor for melanin synthesis in life forms.