Cancer Biology by Professor Rajesh N Gacche
Plant originated drugs/formulations are extensively prescribed by the physicians as a complementa... more Plant originated drugs/formulations are extensively prescribed by the physicians as a complementary therapy for treating various human ailments including cancer. In this study Prosopis juliflora leaves methanol extract was prepared and exposed to human breast cancer cell lines i.e. MDA-MB-231 and MCF-7 and human keratinocytes HaCaT as a representative of normal cells. Initially, a series of in vitro experiments like cell proliferation, migration, colony formation, cell cycle arrest and inhibition of angiogenesis. After confirmation of the efficient and selective activity against triple negative breast cancer cell line, we further evaluated the possible mechanism of inducing cell death and experiments like detection of reactive oxygen species, caspases and poly (ADP-ribose) polymerase cleavage study and Annexin V assay were performed. We also evaluated in vivo anti tumorigenic activity of the P. juliflora leaves by using 4T1 cells (a triple negative mouse origin breast cancer cell line) and BALB/c xenograft mouse model. In vitro experiments revealed that methanol extract of Prosopis juliflora leaves possess impressive anti-breast cancer activity more specifically against triple negative breast cancer cells, while the in vivo studies demonstrated that P. juliflora leaves extract significantly suppressed the 4T1 induced tumor growth. Present investigations clearly focus the significance of P. juliflora as an important resource for finding novel leads against triple negative breast cancer. The results may also act as a ready reference towards developing P. juliflora based formulation as an alternative and complementary medicine for the management of breast cancer.
A B S T R A C T Angiogenesis research in the past two decades has contributed significantly towar... more A B S T R A C T Angiogenesis research in the past two decades has contributed significantly towards understanding the molecular pathophysiology of cancer progression and inspired target-oriented research and pharma industry for the development of novel anti-angiogenic agents. Currently, over eleven drugs targeting angiogenesis have been approved by the FDA for the treatment of various malignancies. Of the registered anti-angiogenic clinical trials until the end of 2017 (ClinicalTrials.gov), over 47% were completed, 10% were terminated, 3% withdrawn, over 0.5% were suspended and only 4 trials have culminated in FDA approval for marketing. On the one hand, the clinical benefits of anti-angiogenic drugs prompted the development of novel anti-angiogenic agents. On the other hand, however, a plethora of recent studies demonstrated the emergence of tumor drug resistance towards currently used anti-angiogenic therapeutics. Series of preclinical and clinical studies have highlighted the enigma of drug resistance with functional bypass pathways, and identified compensatory or alternative angiogenic mechanisms assuring tumor growth in the midst of an anti-angiogenic stress environment. In the present review the classical literature of such redundant angiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described. A strategic discourse regarding increasing tumor drug resistance and future modalities for anti-angiogenic therapy is also discussed in view of recent advances.
Since the establishment of tumor angiogenesis as a therapeutic target, an excitement in developin... more Since the establishment of tumor angiogenesis as a therapeutic target, an excitement in developing the anti-angiogenic agents was resulted in tailoring a humanized monoclonal antibody (Bevacizumab) against vascular endothelial growth factor (VEGF): a key factor in recruiting angiogenesis. The past three decades' research in the area of angiogenesis also invented a series of novel and effective anti-angiogenic agents targeting the VEGF signaling axis. Despite the demonstrable clinical benefits of anti-angiogenic therapy, the preclinical and clinical data of the current therapeutic settings clearly indicate the transient efficacy, restoration of tumor progression and aggressive recurrence of tumor invasion after the withdrawal of anti-angiogenic therapy. Therefore, the impact of this therapeutic regime on improving overall survival of patients has been disappointing in clinic. The recent advances in pathophysiology of tumor angiogenesis and related molecular and cellular underpinnings attributed the conspiracy of compensatory angiogenic pathways in conferring evasive and intrinsic tumor resistance to anti-angiogenic agents. The understandings of how these pathways functionally cross-talk for sustaining tumor angiogenesis during VEGF blockade is essential and perhaps may act as a basic prerequisite for designing novel therapeutic strategies to combat the growing arrogance of tumors toward anti-angiogenic agents. The present review offers a discourse on major compensatory angiogenic pathways operating at cellular and molecular levels and their attributes with resistance to anti-angiogenic agents along with strategic opinions on future setting in targeting tumor angiogenesis.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/authorsrights Formation of new blood vessels (angiogenesis) has been demonstrated to be a basic prerequisite for sustainable growth and proliferation of tumor. Several growth factors, cytokines, small peptides and enzymes support tumor growth either independently or in synergy. Decoding the crucial mechanisms of angiogenesis in physiological and pathological state has remained a subject of intense interest during the past three decades. Currently, the most widely preferred approach for arresting tumor angiogenesis is the blockade of vascular endothelial growth factor (VEGF) pathway; however, the clinical usage of this modality is still limited by several factors such as adverse effects, toxicity, acquired drug resistance, and non-availability of valid biomarkers. Nevertheless, angiogen-esis, being a normal physiological process imposes limitations in maneuvering it as therapeutic target for tumor angiogenesis. The present review offers an updated relevant literature describing the role of well-characterized angiogenic factors, such as VEGF, basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), placenta growth factor (PLGF), hepatocyte growth factor/scatter factor (HGF/SF) and angiopoetins (ANGs) in regulating tumor angiogenesis. We have also attempted to discuss tumor angiogenesis with a perspective of 'an attractive target with emerging challenges', along with the limitations and present status of anti-angiogenic therapy in the current state-of-the-art.
Relationship between structural diversity and biological activities of flavonoids has remained an... more Relationship between structural diversity and biological activities of flavonoids has remained an important discourse in the mainstream of flavonoid research. In the current study anti-angiogenic, cytotoxic, antioxidant and cyclooxygenase (COX) inhibitory activities of diverse class of flavonoids including hydro-xyl and methoxy substituted flavones, flavonones and flavonols have been evaluated in the light of developing flavonoids as a potential scaffold for designing novel anti-antiangiogenic agents. We demonstrate anti-angiogenic potential of flavonoids using in vivo chorioallantoic membrane model (CAM) and further elaborate the possible structural reasoning behind observed anti-angiogenic effect using in silico methods. Additionally, we report antioxidant potential and kinetics of free radical scavenging activity using DPPH and SOR scavenging assays. Current study indicates that selected flavonoids possess considerable COX inhibition potential. Furthermore, we describe cytotoxicity of flavonoids against selected cancer cell lines using MTT cell viability assay. Structural analysis of in silico docking poses and predicted binding free energy values are not only in accordance with the experimental anti-angiogenic CAM values from this study but also are in agreement with the previously reported literature on crystallographic data concerning EGFR and VEGFR inhibition.
Angiogenesis is a key process needed for the growth and survival of solid tumors. Anti-angiogene... more Angiogenesis is a key process needed for the growth and survival of solid tumors. Anti-angiogenesis may arrest the tumor growth and keep check on cancer metastasis. Developing antiangiogenic agents have remained a significant hope in the mainstream of anticancer research. The free radical implications in the initiation of cancers are well established. In the present studies, simple flavone and flavones with hydroxyl substitution in 'A' and 'C' ring at 3, 5, 6, and 7 were studied for antiangiogenic activities using chorioallantoic membrane (CAM) model and kinetics of DPPH (2,2-diphenyl-1-picryl hydrazine) and superoxide anion radical (SOR) scavenging activities. The docking of selected flavones with specific angiogenic targets such as vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF-1) and vascular endothelial growth factor receptor-2 (VEGFR2) from human origin was carried out to focus the possible underlying mechanism of anti-angiogenesis. The result of the present studies shows that the 3-hydroxy substitution of the flavone was found to be the most promising lead for antiangiogenic activity in CAM model. The same was true for DPPH reduction with greater velocity as compared to other hydroxyl substitutions. However the 7-and 6-hydroxy substitution were observed to be more favourable for SOR scavenging activities as compared to other hydroxyl substitutions. The docking experiments shows that the VEGFR2 seems to be a structurally compatible target for tight binding of the flavones especially with 3-hydroxy substitution (−9.78 kcal/mole) as compared to VEGF (−8.47 kcal/mole) and HIF-1 (−8.99 kcal/mole). The quantum chemical descriptors of the test flavones related to free radical scavenging and other biological activities were calculated using computational tools. The data is discussed in the light of structure–activity relationship.
Developing antiangiogenic agents using natural products has remained a significant hope in the ma... more Developing antiangiogenic agents using natural products has remained a significant hope in the mainstream of anticancer research. In the present investigation series of flavonoids possessing di-, tri-, tetra-, and penta-hydroxy substitutions were evaluated as antiangiogenic agents using in vivo choriallantoic membrane model. The MTT-based cyto-toxicity against selected cancer cell lines was carried out to determine the anticancer potential. The kinetics of free radical scavenging activities of these compounds was demonstrated using 2,2-diphenyl-1-picryl hydrazine (DPPH) and superox-ide anion radicals (SORs). To understand the possible anti-angiogenic mechanism, the selected flavonoids were docked in silico onto the proangiogenic peptides such as vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF-1a), and vascular endothelial growth factor receptor-2 (VEGFR2) from human origin. The results of the study shows that amongst the tested flavonoids, genistein (87.1%), kaempferol, (86.3%), and quercetin (84.7%) were found to be effective inhibitors of angiogenesis in CAM model. The antiangiogenic, cytotoxic, and antioxidant activities are discussed in light of structure–activity relationship using in silico approach and other drug-related properties were also calculated using BioMed CAChe V. 6.1.10. The results of the present study focus the isoflavone genistein, kaempferol, and quercetin as lead molecules for designing novel anti-tumor/ antioxidant agents targeting angiogenesis.
Synthesis of metal nanoparticles for improving therapeutic index and drug delivery is coming up a... more Synthesis of metal nanoparticles for improving therapeutic index and drug delivery is coming up as an attractive strategy in the mainstream of cancer therapeutic research. In the present study, curcumin-capped copper nanoparticles (CU-NPs) were evaluated as possible inhibitors of in vivo angiogenesis, pro-angiogenic cytokines involved in promoting tumor angiogenesis along with inhibition of cell proliferation and migration of breast cancer cell line MDA-MB-231. The antiangiogenic potential was assessed using in vivo chorioallantoic membrane (CAM) model. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT)-based cytotoxicity assay was used to assess the effect of CU-NPs against proliferation of breast cancer cell line. The wound healing migration assay was used to evaluate the effects of CU-NPs on the migration ability of breast cancer cell line. Native curcumin (CU) was used as a reference compound for comparison purpose. The result of the present investigation indicates that CU-NPs could not demonstrate impressive antiangiogenic or anticancer activities significantly as compared to native CU. The possible mechanisms of experimental outcomes are discussed in the light of the methods of nanoparticle synthesis in concert with the current state of the art literature.
Medicinal Chemistry Research, 2012
A series of novel curcumin analogues 5am were synthesized by Claisen-Schmidt condensation of vari... more A series of novel curcumin analogues 5am were synthesized by Claisen-Schmidt condensation of various aromatic and heteroaromatic amides of 3-aminoactophenones 4a-m with 3-bromo-2,4,6-trimethoxybenzaldehyde and characterized by IR, 1 H NMR and mass spectroscopic analysis and were evaluated for anti-inflammatory, anti-cancer and anti-oxidant activity. Out of the 13 synthesized compounds, compounds 5f, 5j and 5m were excellent inhibitors of TNF-a and IL-6. Compounds 5c, 5e, 5b and 5d showed potent COX-2 inhibition, compounds 5d and 5f have shown good trypsin inhibition and compounds 5e, 5g and 5c exhibited excellent b-glucuronidase inhibition. Compounds 5l and 5m showed potent anti-cancer activity against selected five human cancer cell lines. All the compounds exhibited moderate free radical scavenging activity, while compounds 5a and 5m were excellent OH radical scavengers.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2013
A series of novel carbazole chalcones has been synthesised and evaluated for radical scavenging a... more A series of novel carbazole chalcones has been synthesised and evaluated for radical scavenging activity, cytotoxicity and antimicrobial activities. Compounds 12m, 12o and 12c exhibited good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, compounds 12e, 12m and 12d were excellent hydroxyl radical scavengers and compounds 12a, 12e, 12g, 12n and 12m have shown inhibition of oxidative DNA damage induced by 2,2′-azobis (2-amidinopropane hydrochloride). Compounds 12j, 12i, 12n, 12c, 12m and 12e were most active against the selected cancer cell lines. Compounds 12a, 12e and 12m showed good antibacterial activity and compounds 12h and 12m have shown good antifungal activity. All the compounds were subjected for absorption, distribution, metabolism and excretion (ADME) predictions by computational method and found that these molecules could be considered as potential candidates for oral drug development.
Indian Journal of Biotechnology
Breast cancer is a prominent disorder that affects mostly mid aged women with a high intensity, u... more Breast cancer is a prominent disorder that affects mostly mid aged women with a high intensity, upsetting every ninth women of ten. The available drugs and treatments fall back as they do not completely eradicate the cancerous cells from body. Hence, newer and more effective drugs and treatments against breast cancer are the need-of-hour. The increased level of estrogen within body increases the chance of breast cancer, whereas the regular concentration plays significant role in normal cell functioning. Melatonin is popularly used as an anti-estrogenic compound, whereas violacein an active secondary metabolite secreted by bacteria like 'Chromobacterium violaceum' has strong structural similarity with melatonin and, thus, possess latency of being tested for its anti-cancerous activity. In the current study, docking and virtual screening was utilized to prove the fact that violacein and similar compounds can bind more efficiently to estrogen receptor than that of melatonin and...
Pyridazinones are widely recognized as versatile scaffolds with a wide spectrum of biological act... more Pyridazinones are widely recognized as versatile scaffolds with a wide spectrum of biological activities.
In the present work, a series of new 4-chloro-2-(3-chloro-4-fluorophenyl)-5-(aliphatic/cyclic saturated
amino)pyridazin-3(2H)-one derivatives 4a–i were synthesized and characterized by spectral techniques.
The inhibitory effects of the synthesized compounds 4a–i on the viability of three human cancer cell
lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds
4a–i screened, 4g and 4i exhibited inhibitory activity very close to the standard methotrexate;
therefore, these lead compounds were further tested for their potential to inhibit the proangiogenic
cytokines involved in tumor progression. Compound 4g was found to be a potent antiangiogenic
agent against TNFa, VEGF, FGFb, and TGFb, whereas 4i showed potent antiangiogenic activity against TNFa,
VEGF, FGFb, and leptin. All the compounds 4a–i were screened for their antioxidant activities using
2,2-diphenyl-1-picryl hydrazine (DPPH), OH, and superoxide anion radicals. Compound 4f showed betterOH
radical scavenging activity than the standard ascorbic acid.
Bioorganic & Medicinal Chemistry Letters, 2010
A series of nitrogen-containing benzophenone analogues were synthesized by Mannich reaction and e... more A series of nitrogen-containing benzophenone analogues were synthesized by Mannich reaction and evaluated for the inhibition of pro-inflammatory cytokines, TNF-a and IL-6. DPPH (1,1-diphenyl-2-picryl hydrazine) radical scavenging activity and its kinetics were studied to determine the antioxidant potential of the test samples. All the synthesized compounds exhibited promising activity against IL-6 in a range of 81-89%, 09-42% at 10 and 1 lM, respectively, concentration. Exceptionally, the compound 20e was observed to be an effective inhibitor of TNF-a (54%) and IL-6 (97%), (47%) at 10 and 1 lM concentrations with minimum toxicity (22%) against CCK-8 cells. With few exceptions, all other compounds were found to be excellent inhibitors of IL-6 and moderate to excellent inhibitors of TNF-a, however the toxicity profiles of these compounds need to be ameliorated in further optimization studies. Amongst the tested compounds, 16a, 17g, 18f, 18g, 19g and 20e were found to possess significant antioxidant activity.
The use of natural substances to inhibit carcinogenesis is a rapidly evolving aspect of cancer re... more The use of natural substances to inhibit carcinogenesis is a rapidly evolving aspect of cancer research. In present investigation the ethanolic extract of Argemone mexicana L., (Papaveraceae), Polyalthia longifolia (Sonner.) Thw. (Annonaceae), Terminalia bellarica (Gaerth.) Roxb. (Combretaceae) and Terminalia chebula Retz. Abs. (Combretaceae) were evaluated for their in vitro anticancer and antimicrobial activity. The results obtained indicates that P. longifolia possess a potential inhibiting activity towards HeLa-B75 [(68.22 ± 0.71)%] HEP-3B [(39.15 ± 0.12)%] and PN-15 [(55.21 ± 0.42)%] cancer cell lines. The selected plant samples were also assessed for their antimicrobial activity against Escherichia coli (DH5-α), Staphylococcus aureus (MTCC 96), Proteus vulgaris (MTCC 1751), and Candida albicans (MTCC 3017) and the minimum inhibitory concentrations (MICs) were determined using microdilution assay. In general, it was observed that the extract of A. mexicana was found to be more effective against selected microbial strains. The results of the present findings may be useful for the discovery of novel anticancer and antimicrobial agents from the plant origin.
Pyridazinones are widely recognized as versatile scaffolds with a wide spectrum of biological act... more Pyridazinones are widely recognized as versatile scaffolds with a wide spectrum of biological activities. In the present work, a series of new 4-chloro-2-(3-chloro-4-fluorophenyl)-5-(aliphatic/cyclic saturated amino)pyridazin-3(2H)-one derivatives 4a-i were synthesized and characterized by spectral techniques. The inhibitory effects of the synthesized compounds 4a-i on the viability of three human cancer cell lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 4a-i screened, 4g and 4i exhibited inhibitory activity very close to the standard methotrexate; therefore, these lead compounds were further tested for their potential to inhibit the proangiogenic cytokines involved in tumor progression. Compound 4g was found to be a potent antiangiogenic agent against TNFa, VEGF, FGFb, and TGFb, whereas 4i showed potent antiangiogenic activity against TNFa, VEGF, FGFb, and leptin. All the compounds 4a-i were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), OH, and superoxide anion radicals. Compound 4f showed better OH radical scavenging activity than the standard ascorbic acid.
Biomedical Research by Professor Rajesh N Gacche
Synthesis of 2(3,5-disubstituted)-1H-pyrazol-4-yl-thio-5-(pyridin-4-yl)1,3,4-oxadiazoles was achi... more Synthesis of 2(3,5-disubstituted)-1H-pyrazol-4-yl-thio-5-(pyridin-4-yl)1,3,4-oxadiazoles was achieved via one pot multi-component reaction of 1-(4-substitutedphenyl)-2-((5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)thio)ethanone, substituted benzaldehydes and hydrazine hydrate by using Bleaching earth clay (pH 12.5, 10 wt%) and Polyethyleneglycol (PEG-400) as a green reaction media. The method is found an efficient, eco-friendly and catalyst recycled for five times with no significant loss in the yield of product. All the synthesized compounds were characterized by spectral data and screened in vitro for their antibacterial and antioxidant activities. The compounds 5s and 5l have shown considerable antioxidant and antimicrobial activity, however all other synthesized compounds demonstrated moderate activities.
Objective: To evaluate the anti-inflammatory activity of flavonoid (Hesperidin 40 mg/kg) on acute... more Objective: To evaluate the anti-inflammatory activity of flavonoid (Hesperidin 40 mg/kg) on acute inflammation (carrageenan-induced paw edema) and chronic inflammation (cotton pellet granuloma) in guinea pigs. Methodology: Studying samples of guinea pigs were divided into three groups. Group I was used as control received 1ml of 5% carboxymethyl cellulose suspension, Hesperidin at a dose of 40 mg/kg was given orally to group II and group III was treated with indomethacin (10 mg/kg). 1.0 ml of carrageenan was injected s.c. to plantar region of right hind paw of each guinea pig. The change in paw volume was measured at 0, 1, 2, 3 and 4 hours intervals. For chronic model of inflammation, sterilized cotton pellets weighing 50±1 mg each, were implanted into both sides of the groin region of each guinea pig, under light anesthesia. Drug treatment was given for 7 days. On the eight day, cotton pellets along with granuloma were removed surgically and wet pellets were weighed, after that dried at 60 0 C overnight and then the weight of dry pellets was taken. Results: The results indicates that Hesperidin at a dose of 40 mg/kg body weight exhibited significant inhibition (P<0.05). The Percent Inhibition with the control, standard (Indomethacin) and the test compound (Hesperidin) were 0%, 74% and 77% in the carrageenan induced paw edema model and were 0%, 37%, and 27% respectively in cotton pellet induced granuloma method. Conclusion: This study concludes that, Hesperidin have significant anti-inflammatory effects in both acute and chronic inflammatory conditions.
Diabetes is embracing the human population in logarithmic fashion both in developed as well as de... more Diabetes is embracing the human population in logarithmic fashion both in developed as well as developing countries. Aldose reductase is one of the important enzymes of polyol pathway of sugar metabolism in humans. Aldose reductase inhibition has been identified as one of the important target for developing novel antidiabetic agents. In this report, we present an effective synthesis of 7-(substituted phenyl) chromeno-pyrano [2,3-d]pyrimidine-6,8,10-(7H,9H,11H)-trione derivatives and demonstrate their aldose reductase inhibition potential in order to identify novel schemes for finding putative aldose reductase inhibitors. The antioxidant activity of all the synthesized compounds with negligible toxicity demonstrates the biological efficacy of the synthesized compounds. The in silico molecular docking and structural analysis of docked poses conducted in the current investigation sheds light on the structural rationale of the observed aldose reductase inhibition by all the newly synthesized compounds.
Introduction: Compounds containing thiadiazole moiety are
cognized to possess with variety of cli... more Introduction: Compounds containing thiadiazole moiety are
cognized to possess with variety of clinical and therapeutic
activity. Finding a suitable drug target for newly synthesized
compounds remain a major bottle neck in current high
throughout medicinal chemistry era.
Aim: To effectively synthesize di substituted thiadiazole compounds
and demonstrate drug target identification using an in
silico pharmacophore probing approach. Moreover, we also aim
to validate the suitability of identified drug target.
Materials and Methods: A cost-effective and environmental
friendly chemical synthesis scheme for production of di
substituted thiadiazole compounds was employed. Target
identification was conducted by Pharmmapper software.
Validation was accomplished by performing molecular docking
and further Molecular Hydrophobic Potential (MHP) analysis.
Results: Pharmacophore probing base approach identified
hepatocyte growth factor receptor (c-Met) as a suitable
biological target for newly synthesized compounds. Binding
free energy values indicate that compound 4b, 4e, 4g and 4h
has tremendous potential to be further used as lead compound
to design selective inhibitors of c-Met receptor. MHP data
from current study supports the possibility that hydrophobic
contacts might act as major factor stabilizing thiadiazole- c-Met
complex. Moreover, in silico observations of current study are
in absolute accordance with previously described in vitro and
crystallographic analysis.
Conclusion: We demonstrate that thiadiazole compounds
synthesized in current investigation has high potential to act
in modulation of hepatocyte growth factor receptor (c-Met)
activity and thereby act as putative therapeutic agent in cancer
therapy.
Diabetes is embracing the human population in logarithmic fashion both in developed as well as de... more Diabetes is embracing the human population in logarithmic fashion both in developed as well as developing countries. Aldose reductase is one of the important enzymes of polyol pathway of sugar metabolism in humans. Aldose reductase inhibition has been identified as one of the important target for developing novel antidiabetic agents. In this report, we present an effective synthesis of 7-(substituted phenyl) chromeno-pyrano [2,3-d]pyrimidine-6,8,10-(7H,9H,11H)-trione derivatives and demonstrate their aldose reductase inhibition potential in order to identify novel schemes for finding putative aldose reductase inhibitors. The antioxidant activity of all the synthesized compounds with negligible toxicity demonstrates the biological efficacy of the synthesized compounds. The in silico molecular docking and structural analysis of docked poses conducted in the current investigation sheds light on the structural rationale of the observed aldose reductase inhibition by all the newly synthesized compounds.
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Cancer Biology by Professor Rajesh N Gacche
In the present work, a series of new 4-chloro-2-(3-chloro-4-fluorophenyl)-5-(aliphatic/cyclic saturated
amino)pyridazin-3(2H)-one derivatives 4a–i were synthesized and characterized by spectral techniques.
The inhibitory effects of the synthesized compounds 4a–i on the viability of three human cancer cell
lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds
4a–i screened, 4g and 4i exhibited inhibitory activity very close to the standard methotrexate;
therefore, these lead compounds were further tested for their potential to inhibit the proangiogenic
cytokines involved in tumor progression. Compound 4g was found to be a potent antiangiogenic
agent against TNFa, VEGF, FGFb, and TGFb, whereas 4i showed potent antiangiogenic activity against TNFa,
VEGF, FGFb, and leptin. All the compounds 4a–i were screened for their antioxidant activities using
2,2-diphenyl-1-picryl hydrazine (DPPH), OH, and superoxide anion radicals. Compound 4f showed betterOH
radical scavenging activity than the standard ascorbic acid.
Biomedical Research by Professor Rajesh N Gacche
cognized to possess with variety of clinical and therapeutic
activity. Finding a suitable drug target for newly synthesized
compounds remain a major bottle neck in current high
throughout medicinal chemistry era.
Aim: To effectively synthesize di substituted thiadiazole compounds
and demonstrate drug target identification using an in
silico pharmacophore probing approach. Moreover, we also aim
to validate the suitability of identified drug target.
Materials and Methods: A cost-effective and environmental
friendly chemical synthesis scheme for production of di
substituted thiadiazole compounds was employed. Target
identification was conducted by Pharmmapper software.
Validation was accomplished by performing molecular docking
and further Molecular Hydrophobic Potential (MHP) analysis.
Results: Pharmacophore probing base approach identified
hepatocyte growth factor receptor (c-Met) as a suitable
biological target for newly synthesized compounds. Binding
free energy values indicate that compound 4b, 4e, 4g and 4h
has tremendous potential to be further used as lead compound
to design selective inhibitors of c-Met receptor. MHP data
from current study supports the possibility that hydrophobic
contacts might act as major factor stabilizing thiadiazole- c-Met
complex. Moreover, in silico observations of current study are
in absolute accordance with previously described in vitro and
crystallographic analysis.
Conclusion: We demonstrate that thiadiazole compounds
synthesized in current investigation has high potential to act
in modulation of hepatocyte growth factor receptor (c-Met)
activity and thereby act as putative therapeutic agent in cancer
therapy.