Applications of the titanium catalyzed cyclocarbonylation towards natural product syntheses

Recently an efficient methodology, a hetero Pauson-Khand reaction, based on titanium-catalyzed cyclocarbonylation of tethered enals for the general preparation of ¥ã-butyrolactone rings, which are typically embedded in polycyclic systems of many natural products was reported. To demonstrate this new strategy, the total syntheses of the natural products asteriscanolide and ginkgolide were investigated. The first part of this work is dedicated to synthetic efforts toward the total synthesis of asteriscanolide. Approaches highlighted by the [2,3]-Wittig rearrangement, the thermal silyloxy-Cope rearrangement, and a titanium-catalyzed cyclocarbonylation, which is the pivotal step to afford the ¥ã-butyrolactone ring. This study firmly established the utility of cyclocarbonylation methodology for the synthesis of complex, polycyclic organic molecules and demonstrates a useful new approach to the stereocontrolled construction of polycyclic, cyclooctanoid natural products. As part of continuing efforts in applying the cyclocarbonylation strategy towards the total synthesis of natural products, ginkgolides were chosen as second target molecules. The precursor for a hetero Pauson-Khand reaction was efficiently synthesized. It was hoped that the titanium mediated reductive cyclization of the precursor would introduce a butenolide moiety of the target model. Unfortunately, the reductive elimination step was unsuccessful. At this point, further tasks to effect reductive elimination on this system remain, in order to advance towards the target molecule

Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity Against Rifampicin-Resistant Mycobacterium tuberculosis

Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy and AIDS related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase (AT) domain of module 6 of rifamycin polyketide synthase (rifPKS) with that of module 2 of rapamycin PKS. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.This research was originally published in the Journal of Biological Chemistry. Nigam, A., Almabruk, K. H., Saxena, A., Yang, J., Mukherjee, U., Kaur, H., ... & Lal, R. Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis. Journal of Biological Chemistry. 2014. 289:21142-21152. © the American Society for Biochemistry and Molecular Biology. This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by The American Society for Biochemistry and Molecular Biology, Inc., and can be found at: http://www.jbc.org/Keywords: Domain Swapping, Polyketide Synthase, Rifamycin analogs, Multiple Drug Resistant, 24-desmethylrifamyci

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

Rationale Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. Objectives Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (−)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. Results Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (Ki=0.71–341 nM) to serotonin (5-HT)₂ₐ but not 5-HT₁ₐ or 5-HT₂c receptors.Mefloquine but not chloroquine was a partial 5-HT₂ₐ agonist and a full 5-HT₂c agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine’s effects. Mefloquine had low or no affinity for dopamine D₁, D₂, D₃, and D₄.₄ receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D₃ receptor and mefloquine but not chloroquine or hallucinogens blocked [³H]5-HT uptake by the 5-HT transporter. Conclusions Mefloquine, but not chloroquine, shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines

Chronic Disease Prediction Model Using Integration of DBSCAN, SMOTE-ENN, and Random Forest

Heart disease (HD) is number one chronic disease and becomes a major cause of worldwide disability and death. Aside of HD, type 2 diabetes (T2D) is also as the most deathful diseases that causes serious issues if untreated and undetected. HD and T2D predictions are the most effective measures to control the HD and T2D. Thus, early HD and T2D predictions are important to help individuals in preventing the occurrence of the worst cases. This study proposes a chronic disease prediction model for HD and T2D prediction. The proposed study utilized random forest combined with DBSCAN as outlier detection method and SMOTE-ENN as data balancing method. Two HD datasets (Statlog and Cleveland) and one T2D dataset (NHIS Korea) were used for building the model and comparing the results with other existing machine learning (ML) algorithms, including GNB, LR, MLP, DT, and SVM. To measure the performance of the model, k-fold (10) cross-validation and several performance metrics including accuracy, precision, f-measure, and recall are applied in this study. The results show the model that we proposed outperforms other classification models, as well as previous studies, with accuracy rates 97.63%, 97.69%, and 94.85% for Statlog HD dataset, Cleveland HD dataset and NHIS T2D dataset, respectively. By utilizing the proposed model, it could increase the expectation in preventing the occurrence of the worst case and helping individuals in taking fast and precise actions when status of HD and T2D are detected

MahmudTaifoPharmacyModificationRifamycinPolyketide(SupplementalData).pdf

Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy and AIDS related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase (AT) domain of module 6 of rifamycin polyketide synthase (rifPKS) with that of module 2 of rapamycin PKS. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.Keywords: Polyketide Synthase, Domain Swapping, 24-desmethylrifamycin, Rifamycin analogs, Multiple Drug ResistantKeywords: Polyketide Synthase, Domain Swapping, 24-desmethylrifamycin, Rifamycin analogs, Multiple Drug Resistan

MahmudTaifoPharmacyModificationRifamycinPolyketide.pdf

Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy and AIDS related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase (AT) domain of module 6 of rifamycin polyketide synthase (rifPKS) with that of module 2 of rapamycin PKS. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.Keywords: Multiple Drug Resistant, Domain Swapping, Polyketide Synthase, Rifamycin analogs, 24-desmethylrifamycinKeywords: Multiple Drug Resistant, Domain Swapping, Polyketide Synthase, Rifamycin analogs, 24-desmethylrifamycinKeywords: Multiple Drug Resistant, Domain Swapping, Polyketide Synthase, Rifamycin analogs, 24-desmethylrifamycinKeywords: Multiple Drug Resistant, Domain Swapping, Polyketide Synthase, Rifamycin analogs, 24-desmethylrifamyci