RESUMO
A series of designed stilbenoid-flavanone hybrids featuring sp3-hybridized C2 and C3 atoms of C-ring was evaluated against colorectal cancers presented compounds 4, 17, and 20 as the most potential compounds among explored compounds. Evaluation of the anticancer activity spectrum of compounds 4, 17, and 20 against diverse solid tumors presented compounds 17 and 20 with interesting anticancer spectrum. The potencies of compounds 17 and 20 were assessed in comparison with FDA-approved anticancer drugs. Compound 17 was the, in general, the most potent showing low micromolar GI50 values that were more potent than the standard FDA-approved drugs against several solid tumors including colon, brain, skin, renal, prostate and breast tumors. Compound 17 was subjected for evaluation against normal cell lines and was subjected to a mechanism study in HCT116 colon cancer cells which presented it as an inhibitor of Wnt signaling pathway triggering G2/M cell cycle arrest though activation of p53-p21 pathway as well as intrinsic and extrinsic apoptotic death of colon cancer cells. Compound 17 might be a candidate for further development against diverse solid tumors including colon cancer.
Assuntos
Antineoplásicos , Neoplasias do Colo , Flavanonas , Iohexol/análogos & derivados , Estilbenos , Masculino , Humanos , Via de Sinalização Wnt , Estilbenos/farmacologia , Antineoplásicos/farmacologia , Células HCT116 , Flavanonas/farmacologia , Apoptose , Neoplasias do Colo/tratamento farmacológico , Proliferação de Células , Linhagem Celular Tumoral , beta Catenina/metabolismoRESUMO
A chromone-peptidyl hybrids series was synthesised and rationally repurposed towards identification of potential antileishmanial hits against visceral leishmaniasis. Three hybrids 7c, 7n, and 7h showed potential IC50 values (9.8, 10, and 12 µM, respectively) which were comparable to erufosine IC50 (9.8 µM) but lower potency than miltefosine IC50 (3.5 µM). Preliminary assessment of cytotoxicity using human THP-1 cells presented chromone-peptidyl hybrids 7c and 7n as non-cytotoxic up to 100 µM while erufosine and miltefosine had CC50 of 19.4 µM and >40 µM, respectively. In silico studies pinpointed the N-p-methoxyphenethyl substituent at the peptidyl moiety together with the oxygen-based substituted functions of the phenyl ring of the chromone moiety as crucial players in binding to LdCALP. Together, these findings present chromone-peptidyl hybrids 7c and 7n as potential and anticipated non-cytotoxic antileishmanial hit compounds for possible development of potential antileishmanial agents against visceral leishmaniasis.
Assuntos
Leishmania donovani , Leishmaniose Visceral , Humanos , CromonasRESUMO
Scaffold hopping of N-benzyl-3,4,5-trimethoxyaniline afforded 5,6,7-trimethoxyflavan derivatives that were efficiently synthesized in four linear steps. As lung cancer is the most lethal cancer, twenty-three synthesized compounds were evaluated against a panel of lung cancer cells. Amongst, compounds 8q and 8e showed interesting activity. Hence, compounds 8q and 8e were evaluated against panels of diverse cancers. Compounds 8q and 8e showed broad spectrum anticancer activity. However, compound 8q was more effective and, hence, was advanced for potency evaluation and characterization. Compound 8q showed comparable potencies to gefitinib, and oxaliplatin against lung and colorectal cancers, respectively, and superior potencies to temozolomide, dacarbazine, cisplatin, enzalutamide, methotrexate, imatinib against brain, skin, ovary, prostate, breast, and blood cancers, respectively. Compound 8q increased cleaved PARP, caspase 3, and 7 inducing apoptosis. In addition, it inhibited cyclins A, B1, H and cdc25c, and increased p53 triggering cell cycle arrest in G2/M phase. Moreover, it decreased YAP and increased LATS1 and p-mob1/mob1 activating hippo signaling. Furthermore, it decreased p-PI3K/PI3k, p-mTOR/mTOR and p-P70S6K/P70S6K inhibiting PI3k pathway. Together, these findings present compound 8q as a potential anticancer lead compound for further development of potential agents.
Assuntos
Antineoplásicos , Neoplasias Pulmonares , Masculino , Feminino , Humanos , Via de Sinalização Hippo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Apoptose , Serina-Treonina Quinases TOR/metabolismo , Proliferação de CélulasRESUMO
A series of rosmarinic acid-ß-amino-α-ketoamide hybrids were synthesized and rationally repurposed towards the identification of new antileishmanial hit compounds. Two hybrids, 2g and 2h, showed promising activity (IC50 values of 9.5 and 8.8 µM against Leishmania donovani promastigotes, respectively). Their activities were comparable to erufosine. In addition, cytotoxicity evaluation employing human THP-1 cells revealed that the two hybrids 2g and 2h possess no cytotoxic effects up to 100 µM, while erufosine possessed cytotoxicity with CC50 value of 19.4 µM. In silico docking provided insights into structure-activity relationship emphasizing the importance of the aliphatic chain at the α-carbon of the cinnamoyl carbonyl group establishing favorable binding interactions with LdCALP and LARG in both hybrids 2g and 2h. In light of these findings, hybrids 2g and 2h are suggested as potential safe antileishmanial hit compounds for further development of anti-leishmanial agents.
RESUMO
The tremendous explosion of image-, video-, and audio-enabled mobile devices, such as tablets and smart-phones in recent years, has led to an associated dramatic increase in the volume of captured and distributed multimedia content. In particular, the number of digital photographs being captured annually is approaching 100 billion in just the U.S. These pictures are increasingly being acquired by inexperienced, casual users under highly diverse conditions leading to a plethora of distortions, including blur induced by camera shake. In order to be able to automatically detect, correct, or cull images impaired by shake-induced blur, it is necessary to develop distortion models specific to and suitable for assessing the sharpness of camera-shaken images. Toward this goal, we have developed a no-reference framework for automatically predicting the perceptual quality of camera-shaken images based on their spectral statistics. Two kinds of features are defined that capture blur induced by camera shake. One is a directional feature, which measures the variation of the image spectrum across orientations. The second feature captures the shape, area, and orientation of the spectral contours of camera shaken images. We demonstrate the performance of an algorithm derived from these features on new and existing databases of images distorted by camera shake.