Applications of Pyrrole and Pyridine-based Heterocycles in Cancer Diagnosis and Treatment.

BACKGROUND: The escalation of cancer worldwide is one of the major causes of economy burden and loss of human resources. According to the American Cancer Society, there will be 1,958,310 new cancer cases and 609,820 projected cancer deaths in 2023 in the United States. It is projected that by 2040, the burden of global cancer is expected to rise to 29.5 million per year, causing a death toll of 16.4 million. The hemostasis regulation by cellular protein synthesis and their targeted degradation is required for normal cell growth. The imbalance in hemostasis causes unbridled growth in cells and results in cancer. The DNA of cells needs to be targeted by chemotherapeutic agents for cancer treatment, but at the same time, their efficacy and toxicity also need to be considered for successful treatment. OBJECTIVE: The objective of this study is to review the published work on pyrrole and pyridine, which have been prominent in the diagnosis and possess anticancer activity, to obtain some novel lead molecules of improved cancer therapeutic. METHODS: A literature search was carried out using different search engines, like Sci-finder, Elsevier, ScienceDirect, RSC etc., for small molecules based on pyrrole and pyridine helpful in diagnosis and inducing apoptosis in cancer cells. The research findings on the application of these compounds from 2018-2023 were reviewed on a variety of cell lines, such as breast cancer, liver cancer, epithelial cancer, etc. Results: In this review, the published small molecules, pyrrole and pyridine and their derivatives, which have roles in the diagnosis and treatment of cancers, were discussed to provide some insight into the structural features responsible for diagnosis and treatment. The analogues with the chromeno-furo-pyridine skeleton showed the highest anticancer activity against breast cancer. The compound 5-amino-N-(1-(pyridin-4- yl)ethylidene)-1H-pyrazole-4-carbohydrazides was highly potent against HEPG2 cancer cell. Redaporfin is used for the treatment of cholangiocarcinoma, biliary tract cancer, cisplatin-resistant head and neck squamous cell carcinoma, and pigmentation melanoma, and it is in clinical trials for phase II. These structural features present a high potential for designing novel anticancer agents for diagnosis and drug development. CONCLUSION: Therefore, the N- and C-substituted pyrrole and pyridine-based novel privileged small Nheterocyclic scaffolds are potential molecules used in the diagnosis and treatment of cancer. This review discusses the reports on the synthesis of such molecules during 2018-2023. The review mainly discusses various diagnostic techniques for cancer, which employ pyrrole and pyridine heterocyclic scaffolds. Furthermore, the anticancer activity of N- and C-substituted pyrrole and pyridine-based scaffolds has been described, which works against different cancer cell lines, such as MCF-7, A549, A2780, HepG2, MDA-MB-231, K562, HT- 29, Caco-2 cells, Hela, Huh-7, WSU-DLCL2, HCT-116, HBL-100, H23, HCC827, SKOV3, etc. This review will help the researchers to obtain a critical insight into the structural aspects of pyrrole and pyridine-based scaffolds useful in cancer diagnosis as well as treatment and design pathways to develop novel drugs in the future.

Improved production of alkaline and solvent-stable proteases from a halotolerant Exiguobacterium isolate through heterologous expression.

Halophiles are excellent sources of detergent proteases that are attributed to stability in alkaline pH, salts, surfactants, and hydrophobic solvents. The lower enzymatic yields and tedious downstream processes necessitate the search for newer halophilic sources. We have previously reported a halotolerant Exiguobacterium sp. TBG-PICH-001, which secretes solvent-tolerant alkaline protease/s. The present study describes the heterologous expression of two protease genes, namely, rsep metalloprotease (WP_195864791, 1.23 Kb) and tpa serine protease (WP_195864453, 0.879 Kb) genes. These were cloned into the pET 22b + plasmid vector and expressed in Escherichia coli BL21(DE3). The recombinant proteases rsep and tpa showed respective yields of 6.3 and 6.7 IU/mg, 11 and 12-fold higher than the crude native protease/s from TBG-PICH-001. These showed soluble expression at 46 and 32 KDa, respectively. These were purified to homogeneity through Ni-NTA-affinity chromatography. The purified proteases were characterized for properties like pH & temperature optima and stability, substrate specificity, kinetic parameters, and detergent attributes. They showed affinity towards various substrates with a respective Km of 392 and 301 µM towards casein. The recombinant proteases exhibited stability in the alkaline pH (7-10), surfactants, metal ions, detergents, and hydrophobic solvents, rendering their suitability as detergent additives.

Pan-genomic comparison of a potential solvent-tolerant alkaline protease-producing Exiguobacterium sp. TBG-PICH-001 isolated from a marine habitat.

The identification and applicability of bacteria are inconclusive until comprehended with genomic repositories. Our isolate, Exiguobacterium sp. TBG-PICH-001 exhibited excellent halo- and organic solvent tolerance with simultaneous production of alkaline protease/s (0.512 IU/mL). The crude protease (1 IU) showed a 43.57% degradation of whey protein. The bulk proteins in the whey were hydrolyzed to smaller peptides which were evident in the SDS-PAGE profile. With such characteristics, the isolate became interesting for its genomic studies. The TBG-PICH-001 genome was found to be 3.14 Mb in size with 17 contigs and 47.33% GC content. The genome showed 3176 coding genes, and 2699 genes were characterized for their functionality. The Next-Generation-Sequencing of the genome identified only the isolate's genus; hence we attempted to delineate its species position. The genomes of the isolate and other representative Exiguobacterium spp. were compared based on orthologous genes (Orthovenn2 server). A pan-genomic analysis revealed the match of TBG-PICH-001 with 15 uncharacterized Exiguobacterium genomes at the species level. All these collectively matched with Exiguobacterium indicum, and the results were reconfirmed through phylogenetic studies. Further, the Exiguobacterium indicum genomes were engaged for homology studies rendering 11 classes of protease genes. Two putative proteases (Zinc metalloprotease and Serine protease) obtained from homology were checked for PCR amplification using genomic DNA of TBG-PICH-001 and other Exiguobacterium genomes. The results showed amplification only in the Exiguobacterium indicum genome. These protease genes, after sequencing, were matched with the TBG-PICH-001 genome. Their presence in its whole genome experimentally validated the study. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03796-5.

Integrated fermentative production and downstream processing of L-malic acid by Aspergillus wentii using cassava peel waste.

L-malic acid (L-MA) is an industrially significant chemical with enormous potential. The fungal cell factories could be exploited to harvest it on large scales. In our study, Aspergillus wentii strain (MTCC 1901 T) was explored for L-MA production. Initially, the L-MA production was carried out using glucose with optimization of parameters influencing product accumulation (pH and CaCO3). The fermentation resulted in L-MA titer of 37.9 g/L with 0.39 g/g yield. Then, cassava peel waste (CPW) was used for L-MA production by separate hydrolysis and fermentation. Optimized acidic and enzymatic hydrolysis resulted in glucose release of 0.53 and 0.66 g/g CPW, respectively. The strain accumulated 20.9 g/L and 33.1 g/L L-MA with corresponding yields of 0.25 g/g and 0.34 g/g during batch cultivation using acid and enzyme hydrolysate, respectively. Finally, the produced L-MA was separated using an inexpensive solvent extraction method. Among various solvents used, n-butanol exhibited maximum L-MA extraction efficiency (31%).

Caspase-3 Activators as Anticancer Agents.

BACKGROUND: The cancer is still a major cause of death worldwide. Among different targets to design anticancer agents, caspase-3 is an important target as its cleavage and activation lead to apoptosis and finally, cancer cell death. Apart from some naturally occurring molecules, many small molecules have been reported as caspase-3 activators. OBJECTIVES: In view of the above, the objective has been to review the published work on small molecules reported as caspase-3 activators and their anticancer activity to get some novel lead molecules for designing novel molecules of improved cancer therapeutic. METHODS: Literature search has been carried out using different search engines like google, Elsevier, Science direct, RSC, etc. for the publications of small molecules as caspase-3 activators inducing apoptosis in cancer cells. RESULTS: In this review, the small molecules showing caspase-3 cleavage and activation have been discussed under different broad chemical classes so as to provide some insight into the structural features responsible for caspase-3 activation leading to anticancer activity. The review also encompasses the established drugs, novel organometallics showing caspase-3 activation and anticancer activity. CONCLUSION: A large number of small molecules including some established drugs and organometallics have shown cleavage and activation of caspase-3 leading to apoptosis and anticancer activity. Many reported potent molecules of different chemical classes may be useful as lead molecules for optimization of anticancer activity as well as they may provide an insight of structural features which may be useful in designing novel caspase-3 activators as anticancer agents for drug development.

Microbial carbonic anhydrase mediated carbon capture, sequestration & utilization: A sustainable approach to delivering bio-renewables.

In the recent scenario, anthropogenic interventions have alarmingly disrupted climatic conditions. The persistent change in the climate necessitates carbon neutrality. Efficient ways of carbon capture and sequestration could be employed for sustainable product generation. Carbonic anhydrase (CA) is an enzyme that reversibly catalyzes the conversion of carbon dioxide to bicarbonate ions, further utilized by cells for metabolic processes. Hence, utilizing CA from microbial sources for carbon sequestration and the corresponding delivery of bio-renewables could be the eco-friendly approach. Consequently, the microbial CA and amine-based carbon capture chemicals are synergistically applied to enhance carbon capture efficiency and eventual utilization. This review comprehends recent developments coupled with engineering techniques, especially in microbial CA, to create integrated systems for CO2 sequestration. It envisages developing sustainable approaches towards mitigating environmental CO2 from industries and fossil fuels to generate bio-renewables and other value-added chemicals.

Electrochemical Performance of High-Valence Mo6+ and Low-Valence Mn2+ Doped- Na3 V2 (PO4 )3 @C Cathode for Sodium-Ion Batteries.

The sodium superionic conductor (NASICON)-Na3 V2 (PO4 )3 (NVP) is an attractive cathode for sodium-ion batteries, which is still confronted with limited rate performance due to its low electronic conductivity. In this paper, a chemical strategy is adopted to partially replace V3+ of the NVP framework by low-valence Mn2+ and high-valence Mo6+ substitution. The crystal structure, sodium-ion diffusion coefficient and electrochemical performance of Mn-Mo-doped [Na3.94 V0.98 Mo0.02 Mn(PO4 )3 @C] cathode were investigated. X-ray diffraction confirmed the NASICON-type structure and XPS analysis confirmed the oxidation state of Mn and Mo in doped NVP cathode. The Na ion diffusion processes were inferred from Cyclic Voltammetry (CV), Galvanostatic intermittent titration technique (GITT) and Electrochemical Impedance Spectroscopy (EIS) measurement, which clearly show rapid Na-ion diffusion in NASICON-type cathode materials. The Mn-Mo-substituted NVP shows smoother charge-discharge profiles, improved rate performance (64.80 mAh/g at 1 C rate), better energy density (308.61 mWh/g) and superior Na-ion kinetics than that of unsubstituted NVP@C cathode. Their enhanced performance is attributed to large interstitial volume mainly created by high valence Mo6+ and enhanced capacity is attributed to the low valence Mn2+ doping. These results demonstrate that Mn-Mo-doped NVP cathode is strongly promising cathode material for sodium-ion batteries.

Genome Sequence Analysis of Exiguobacterium sp. Strain TBG-PICH-001, Isolated from Pichavaram Mangrove Forest in South India.

The draft genome sequence of Exiguobacterium sp. strain TBG-PICH-001, isolated from Pichavaram Mangrove Forest (Tamil Nadu, India), is reported here. Paired-end sequencing technology was used to sequence the genome on the Illumina HiSeq X Ten platform. The genome comprises 3,141,454 bp; it harbors 3,154 genes and has a G+C content of 47.34%.

Evidence of C--F-P and aromatic π--F-P weak interactions in imidazolium ionic liquids and its consequences.

A simple change from alkyl group to alkene in side chain of imidazolium cation with same anion resulted in a drastic impact on physical properties (e.g., melting point) from bmimPF6 IL to cmimPF6 IL. The underlying reasons have been elucidated by structural and interaction studies with the help of DSC, SCXRD, vibrational and multi-nuclear NMR spectroscopic techniques. Experiments reveal existence of new weak interactions involving the carbon and π cloud of the imidazolium aromatic ring with fluoride of PF6 anion (i.e., C2--F-P and π--F-P) in cmimPF6 but are absent in structurally similar prototype IL, bmimPF6. Though weak, these interactions helped to form ladder type supramolecular arrangement, resulting in quite high melting point for cmimPF6 IL compared to bmimPF6 IL. These findings emphasize that an IL system can behave uniquely because of the existence of uncommon weak interactions.

A 2D Panoramic Surgical Stent Imaging: Complete Arch Mandibular Implant Fixed Prosthesis along with Bar Supported Maxillary over Denture.

Successful rehabilitation of a patient should restore function, esthetic, and speech by prosthesis. Treatment modalities vary from patient to patient. Semi-precision attachments and implants offer several advantages over the traditional approach. The aim and objective of this report was to assess a case of a 55-year-old female patient who had lost all her teeth, except maxillary canines #13 and #23 and with severe bone loss in the mandible. Tooth-supported bar attachment was planned for maxilla, and a total of five dental implants were placed in the mandible using a flapless approach aided by radiographic gutta-percha surgical stents over panoramic two-dimensional imaging. Customized, radiographic stents help for the placement of implant in the view of paralleling and flapless surgery, completely. An immediate loading protocol is adopted as from day of the surgery to 6 weeks along with implant supported full arch fixed dentures after 4 months. The outcome of the treatment was impressive, and the patient gave a positive response with superb esthetics and functions.

Complementing Crystallography with Ultralow-Frequency Raman Spectroscopy: Structural Insights into Nitrile-Functionalized Ionic Liquids.

Functionalized ionic liquids are a subclass of ionic liquids that are tailored for a specific application. Structural characterization in both solid and liquid phases is central to understanding their physical properties. Here, we used ultralow-frequency Raman spectroscopy, which can measure Raman spectra down to approximately 5 cm(-1) , to study the structures and physical properties of 1-(4-cyanobenzyl)-3-methylimidazolium salts with five different anions. A comparison of the observed low-frequency Raman spectral patterns enabled us to predict the crystal symmetry of one of the synthesized salts for which single-crystal X-ray diffraction data were unobtainable. Real-time tracking of the low-frequency Raman spectral changes during melting revealed peak shifts indicative of different degrees of microscopic heterogeneity in the ionic liquids. The results show that our method provides a facile means that is complementary to X-ray crystallography, for obtaining structural information of ionic liquids.

Heteroleptic dipyrrinato complexes containing 5-ferrocenyldipyrromethene and dithiocarbamates as coligands: selective chromogenic and redox probes.

Six heteroleptic dipyrrinato complexes [Ni(fcdpm)(dedtc)] (1), [Ni(fcdpm)(dipdtc)] (2), [Ni(fcdpm)(dbdtc)] (3), [Pd(fcdpm)(dedtc)] (4), [Pd(fcdpm)(dipdtc)] (5), and [Pd(fcdpm)(dbdtc)] (6) (fcdpm = 5-ferrocenyldipyrromethene; dedtc = diethyldithiocarbamate; dipdtc = diisopropyldithiocarbamate; dbdtc = dibutyldithiocarbamate) have been synthesized and characterized by elemental analyses and spectral (ESI-MS, IR, (1)H, (13)C NMR, UV-vis) and electrochemical studies. Crystal structures of 1, 2, 4, and 5 have been authenticated by X-ray single-crystal analyses. Nickel-based complexes 1-3 display selective chromogenic and redox sensing for Hg(2+) and Pb(2+) ions, while palladium complexes 4-6 display selective chromogenic and redox sensing only for Hg(2+). Electronic absorption, ESI-MS, and electrochemical studies indicated that sensing arises from interaction between 1-3 and Hg(2+)/Pb(2+) through sulfur of the coordinated dithiocarbamates, while it arises from the pyrrolic nitrogen of fcdpm and dithiocarbamate sulfur from 4-6 and Hg(2+). Different modes of binding between Ni and Pd complexes have further been supported by theoretical studies. The receptor-cation binding constants (K(a)) and stoichiometry between probes and Hg(2+)/Pb(2+) have been estimated by the Benesi-Hildebrand method and Job's plot analysis. Detection limits for 1-3 toward Hg(2+)/Pb(2+) and 4-6 for Hg(2+) have been found to be reasonably high.

Inter- and intramolecular Mitsunobu reaction and metal complexation study: synthesis of S-amino acids derived chiral 1,2,3,4-tetrahydroquinoxaline, benzo-annulated [9]-N3 peraza, [12]-N4 peraza-macrocycles.

Substituted 1,2,3,4-tetrahydroquinoxaline, benzo-annulated unsymmetrical chiral [9]-N(3) peraza, and [12]-N(4) peraza-macrocycles have been synthesized employing an inter- and intramolecular Mitsunobu reaction from an amino acid derived common synthetic intermediate 3. The metal complexation study of these macrocycles has been investigated by UV-visible spectroscopic technique with binding constant (K(b)) value 1.84 × 10(3) dm(3) mol(-1) using the Benesi-Hildebrand equation and a Gibbs free energy (ΔG) -19.4 kJ mol(-1) at 35 °C for 14d with Co(2+). The binding properties of the metal were dependent on the structure of polyaza-macrocycles that were confirmed by the DFT optimized structure of two macrocycles. A detailed investigaton of UV-visible spectra of macrocycles and their complete interpretation with the help of TD-DFT along with the frontier molecular orbital calculations are presented.