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SHetA2 (NSC 721689), our lead Flex-Het anti-cancer agent, consists of a thiochroman (Ring A) and a 4-nitrophenyl (Ring B) linked by a thiourea bridge. In this work, several series of new analogs having a tetrahydroquinoline (THQ, Ring A) unit connected by a urea or thiourea linker to a 4-substituted phenyl (Ring B) have been prepared and evaluated relative to SHetA2 in terms of binding affinity with mortalin and inhibition of A2780 ovarian cancer cells. Six of the derivatives equaled or exceeded the efficacy shown by SHetA2. Compounds 1a-d (series 1), lacking a methyl on the Ring A nitrogen and the gem-dimethyls on the adjacent carbon, showed only weak activity. Salt 2, the quaternized N,N-dimethyl iodide salt analog of 1a, also possessed very modest growth inhibition in the cell line studied. Series 3 compounds, which had a C3 ketone and an N-methyl replacing the sulfur in Ring A, were most successful. Compound 3a [Ring A = 1,2,2,4,4-pentamethyl-3-oxo-1,2,3,4-tetrahydroquinolin-6-yl; urea linker; Ring B = 4-nitrophenyl] had slightly lower potency (IC 50 3.8 μM), but better efficacy (94.8%) than SHetA2 (IC 50 3.17 μM, efficacy 84.3%). In addition, 3c and 3d [urea and thiourea linkers, respectively; Ring B = 4-(trifluoromethyl)phenyl] and 3e and 3f [urea and thiourea linkers, respectively; Ring B = 4-(trifluoromethoxy)phenyl] were also evaluated since these agents possessed electron-withdrawing groups with H-bonding capability. All displayed good activity. Compounds 3c and 3e showed improvement in both potency and efficacy compared to SHetA2. In general, when the linker group between Rings A and B was a urea, efficacy values slightly exceeded those with a thiourea linker in the carbonyl-containing THQ systems 3a-g. In contrast, when Ring A possessed the 1,2,2,4,4-pentamethyl-3-hydroxytetrahydroquinolin-6-yl unit (4a-f, series 4), very modest potency and efficacy was observed. Model compound 5, an exact N-methyl THQ analog of SHetA2, demonstrated less potency (IC 50 4.5 μM), but improved efficacy (91.7%). Modeling studies were performed to rationalize the observed results., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- and 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell.

An efficient route to substituted 1-aryl-1 H -indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (S N Ar) ring closure in 45-90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73-96%), while the benzaldehyde series (63-73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1 H -indazole formation without the limiting substitution patterns required for the S N Ar cyclization has also been achieved in 62-78% yields. A selection of 1-aryl-1 H -indazoles was prepared in high yield by a procedure that requires only a single laboratory operation., Competing Interests: The authors declare no conflicts of interest.

Very few cases of placental site trophoblastic tumor (PSTT) primarily involving extrauterine sites have been reported to date. We report a case of a 29-year-old female who presented with a vaginal nodule 9 months after delivery at an outside hospital which was initially diagnosed as a poorly differentiated squamous cell carcinoma. Subsequently she was referred to our institute, and on the basis of histology, mildly elevated serum β-HCG level, and immunohistochemistry, PSTT was diagnosed. After the completion of chemotherapy, the vaginal nodule completely regressed and serum β-hCG returned to baseline. Her follow-up has been unremarkable. This case highlights the importance of the fact that PSTT can be easily misdiagnosed at extrauterine sites in the absence of proper clinical, histologic, and immunohistochemical correlation.

Objective/background: May-Hegglin anomaly (MHA) is a rare familial bleeding disorder characterized by a triad of thrombocytopenia, giant platelets, and Döhle-like inclusion bodies within the leukocytes. The clinical spectrum as well as the pathophysiology of this entity is not well defined. The objective of this work is to present a series of three cases of MHA diagnosed in our hospital, where the patients presented with variable bleeding manifestations, thrombocytopenia, and giant platelets., Materials and Methods: We studied three cases of possible MHA. In addition to the clinical examination, complete hemogram, and peripheral blood smear examination, these patients were also subjected to coagulation studies. Although bleeding symptoms varied among these patients, platelet aggregation tests with various agonists showed a normal response., Results: Consistent findings of this entity noted in our patients were mild-to-moderate thrombocytopenia, giant platelets, and Döhle-like inclusions within the leukocytes., Conclusion: A diagnosis of MHA could be made based on a thorough peripheral blood smear examination, which also helps to avoid a misdiagnosis of immune thrombocytopenia., (Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Acute myeloid leukemia (AML) is a malignant hematopoietic stem cell disorder which is sub-classified based on bone marrow morphology and the presence of specific genetic abnormalities. One such cytogenetic abnormality is the pericentric inversion (inv) of chromosome 16 which is typically seen in AML M4 with eosinophilia and is associated with a favorable prognosis. We report the inv (16) in a young woman with AML M5 and abnormal eosinophils. This is a rare entity with only about 20 cases being reported till date.

Flexible Heteroarotinoids (Flex-Hets) are a class of substituted di-aryl compounds that exhibit potent anti-cancer activity without toxicity. They were derived from the more conformationally restricted, 2-atom linker Hets by substitution of the 2-atom linker with a 3-atom urea or thiourea linker, which conferred more potent inhibitory activity against cancer cell lines. The objectives of this structure activity relationship (SAR) study were to determine if a 4-atom acrylamide linker and various substitutions on the terminal aryl ring altered the anti-cancer activity of these second generation Flex-Het compounds compared to the parent Flex-Het compound, SHetA2, which has a thiourea linker and a nitro substituent. Biological activity was measured using a cytotoxicity assay of the human A2780 ovarian cancer cell line treated with a range of compound concentrations. Nitrogen-based substitutions on the terminal aryl group caused similar, but slightly reduced efficacies and potencies. Exceptions were systems that had a nitro group at the para position, the potencies of which were better than that of SHetA2 with efficacies that were only slightly reduced compared to SHetA2. Similarly, the potency of the system with a para dimethylamino group was greater than that of SHetA2. However, a 30% reduction in efficacy compared to SHetA2 was noted. While specific members with the 4-atom acrylamide linker did exhibit excellent potency, the efficacy was slightly below that of SHetA2. Thus, a gradient of activities was observed as the substituent on the aryl ring was altered., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)