Efficient Synthesis of a Series of Novel Octahydroquinazoline-5-ones via a Simple on-Water Urea-Catalyzed Chemoselective Five-Component Reaction

Multicomponent reactions (MCRs) have become a powerful tool for drug discovery and development owing to their advantages of fast and efficient construction of a large library of products with complexity and diversity. However, conventional MCRs usually proceed in environmentally unfriendly organic solvents rather than in water, a green solvent used by nature for biological chemistry. Herein, a simple and efficient on-water urea-catalyzed chemoselective five-component reaction (5CR) has been developed for the synthesis of a series of novel octahydroquinazoline-5-ones (6), the derivatives of quinazolinones possessing diverse biological activities. The molecular structure of 6{1,1,12} has been confirmed by single-crystal X-ray diffraction. The 5CR can proceed at room temperature under normal atmospheric pressure in good yields and afford a large library of octahydroquinazoline-5-ones with various aromatic and aliphatic substituents at N-1, C-2, and N-3. In addition, a green method has been developed for the synthesis of enaminones, important intermediates in the 5CR and in synthetic chemistry

Instant Inhibition and Subsequent Self-Adaptation of Chlorella sp. Toward Free Ammonia Shock in Wastewater: Physiological and Genetic Responses

Free ammonia (FA) has been recently demonstrated as the primary stress factor suppressing microalgal activities in high-ammonium wastewater. However, its inhibition mechanism and microalgal self-adaptive regulations remain unknown. This study revealed an initial inhibition and subsequent self-adaptation of a wastewater-indigenous Chlorella sp. exposed to FA shock. Mutual physiological and transcriptome analysis indicated that genetic information processing, photosynthesis, and nutrient metabolism were the most influenced metabolic processes. Specifically, for the inhibition behavior, DNA damage was indicated by the significantly up-regulated related genes, leading to the activation of cell cycle checkpoints, programmed apoptosis, and suppressed microalgal growth; FA shock inhibited the photosynthetic activities including both light and dark reactions and photoprotection through non-photochemical quenching; ammonium uptake was also suppressed with the inhibited glutamine synthetase/glutamine α-oxoglutarate aminotransferase cycle and the inactivated glutamate dehydrogenase pathway. With respect to microalgal self-adaptation, DNA damage possibly enhanced overall cell viability through reprogramming the cell fate; recovered nutrient uptake provided substances for self-adaptation activities including amino acid biosynthesis, energy production and storage, and genetic information processing; elevated light reactions further promoted self-adaptation through photodamage repair, photoprotection, and antioxidant systems. These findings enrich our knowledge of microalgal molecular responses to FA shock, facilitating the development of engineering optimization strategies for the microalgal wastewater bioremediation system

Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity

Natural product evodiamine is a multitargeting antitumor lead compound. However, clinical development of evodiamine derivatives was hampered by poor water solubility and limited in vivo antitumor potency. Herein, a series of evodiamine–glucose conjugates were designed by additional targeting glucose transporter-1 (GLUT1). Compared with the lead compound, conjugate 8 exhibited obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also led to lower cytotoxicity to normal cells. Antitumor mechanism studies manifested that conjugate 8 acted by Top1/Top2 dual inhibition, apoptosis induction, and G2/M cell cycle arrest, which selectively targeted tumor cells with a high expression level of GLUT1. Thus, evodiamine–glucose conjugates showed promising features as potential antitumor agents

Enhanced Secretions of Algal Cell-Adhesion Molecules and Metal Ion-Binding Exoproteins Promote Self-Flocculation of Chlorella sp. Cultivated in Municipal Wastewater

The mechanism of self-flocculation remains unclear, partially impeding its efficiency enhancement and commercial application of microalgae-based municipal wastewater (MW) bioremediation technology. This study revealed the contributions of exoproteins [PN, proteins in extracellular polymeric substances (EPS)] to the separation of indigenous microalgae from treated MW. Compared to the low light intensity group, the high light intensity (HL) group produced Chlorella sp. with 4.3-fold higher self-flocculation efficiencies (SE). This was attributed to the enriched biological functions and positional rearrangement of increased PN within 2.9-fold higher EPS. Specifically, a total of 75 PN was over-expressed in the HL group among the 129 PN identified through label-free proteomics. The algal cell-adhesion molecules (Algal-CAMs) and metal-ion-binding PN were demonstrated as two dominant contributors promoting cell adhesion and bridging, through function prediction based on the contained domains. The modeled 3D structure showed that Algal-CAMs presented less hydrophilic α-helix abundance and were distributed in the outermost position of the EPS matrix, further facilitating microalgal separation. Moreover, the 10.1% lower hydrophily degree value, negative interfacial free energy (−19.5 mJ/m2), and 6.8-fold lower energy barrier between cells also supported the observed higher SE. This finding is expected to further fill the knowledge gap of the role of PN in microalgal self-flocculation and promote the development of biomass recovery from the microalgae-wastewater system

Efficient Synthesis of a Series of Novel Octahydroquinazoline-5-ones via a Simple on-Water Urea-Catalyzed Chemoselective Five-Component Reaction

Multicomponent reactions (MCRs) have become a powerful tool for drug discovery and development owing to their advantages of fast and efficient construction of a large library of products with complexity and diversity. However, conventional MCRs usually proceed in environmentally unfriendly organic solvents rather than in water, a green solvent used by nature for biological chemistry. Herein, a simple and efficient on-water urea-catalyzed chemoselective five-component reaction (5CR) has been developed for the synthesis of a series of novel octahydroquinazoline-5-ones (<b>6</b>), the derivatives of quinazolinones possessing diverse biological activities. The molecular structure of <b>6</b>{<i>1,1,12</i>} has been confirmed by single-crystal X-ray diffraction. The 5CR can proceed at room temperature under normal atmospheric pressure in good yields and afford a large library of octahydroquinazoline-5-ones with various aromatic and aliphatic substituents at N-1, C-2, and N-3. In addition, a green method has been developed for the synthesis of enaminones, important intermediates in the 5CR and in synthetic chemistry

Enhanced Secretions of Algal Cell-Adhesion Molecules and Metal Ion-Binding Exoproteins Promote Self-Flocculation of Chlorella sp. Cultivated in Municipal Wastewater

The mechanism of self-flocculation remains unclear, partially impeding its efficiency enhancement and commercial application of microalgae-based municipal wastewater (MW) bioremediation technology. This study revealed the contributions of exoproteins [PN, proteins in extracellular polymeric substances (EPS)] to the separation of indigenous microalgae from treated MW. Compared to the low light intensity group, the high light intensity (HL) group produced Chlorella sp. with 4.3-fold higher self-flocculation efficiencies (SE). This was attributed to the enriched biological functions and positional rearrangement of increased PN within 2.9-fold higher EPS. Specifically, a total of 75 PN was over-expressed in the HL group among the 129 PN identified through label-free proteomics. The algal cell-adhesion molecules (Algal-CAMs) and metal-ion-binding PN were demonstrated as two dominant contributors promoting cell adhesion and bridging, through function prediction based on the contained domains. The modeled 3D structure showed that Algal-CAMs presented less hydrophilic α-helix abundance and were distributed in the outermost position of the EPS matrix, further facilitating microalgal separation. Moreover, the 10.1% lower hydrophily degree value, negative interfacial free energy (−19.5 mJ/m2), and 6.8-fold lower energy barrier between cells also supported the observed higher SE. This finding is expected to further fill the knowledge gap of the role of PN in microalgal self-flocculation and promote the development of biomass recovery from the microalgae-wastewater system

Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity

Natural product evodiamine is a multitargeting antitumor lead compound. However, clinical development of evodiamine derivatives was hampered by poor water solubility and limited in vivo antitumor potency. Herein, a series of evodiamine–glucose conjugates were designed by additional targeting glucose transporter-1 (GLUT1). Compared with the lead compound, conjugate 8 exhibited obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also led to lower cytotoxicity to normal cells. Antitumor mechanism studies manifested that conjugate 8 acted by Top1/Top2 dual inhibition, apoptosis induction, and G2/M cell cycle arrest, which selectively targeted tumor cells with a high expression level of GLUT1. Thus, evodiamine–glucose conjugates showed promising features as potential antitumor agents

Preparation of a Self-Assembled Rhein–Doxorubicin Nanogel Targeting Mitochondria and Investigation on Its Antihepatoma Activity

Mitochondria are involved in the regulation of apoptosis, making them a promising target for the development of new anticancer drugs. Doxorubicin (DOX), a chemotherapeutic drug, can induce reactive oxygen species (ROS)-mediated apoptosis, improving its anticancer effects. Herein, Rhein, an active ingredient in rhubarb, with the capability of self-assembly and mitochondrial targeting, was used in conjunction with DOX to form efficient nanomaterials (Rhein–DOX nanogel) capable of sustained drug release. It was self-assembled with a hydrogen bond, π–π stacking interactions, and hydrophobic interactions as the main driving force, and its loading efficiency was up to 100%. Based on its self-assembly characteristics, we evaluated the mechanism of this material to target mitochondria, induce ROS production, and promote apoptosis. The IC50 of the Rhein–DOX nanogel (3.74 μM) was only 46.3% of that of DOX (11.89 μM), and the tumor inhibition rate of the Rhein–DOX nanogel was 79.4% in vivo, 2.3 times that of DOX. This study not only addresses the disadvantages of high toxicity of DOX and low bioavailability of Rhein, when DOX and Rhein are combined for the treatment of hepatoma, but it also significantly improved the synergistic antihepatoma efficacy of Rhein and DOX, which provides a new idea for the development of long-term antihepatoma agents with low toxicity

Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity

Natural product evodiamine is a multitargeting antitumor lead compound. However, clinical development of evodiamine derivatives was hampered by poor water solubility and limited in vivo antitumor potency. Herein, a series of evodiamine–glucose conjugates were designed by additional targeting glucose transporter-1 (GLUT1). Compared with the lead compound, conjugate 8 exhibited obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also led to lower cytotoxicity to normal cells. Antitumor mechanism studies manifested that conjugate 8 acted by Top1/Top2 dual inhibition, apoptosis induction, and G2/M cell cycle arrest, which selectively targeted tumor cells with a high expression level of GLUT1. Thus, evodiamine–glucose conjugates showed promising features as potential antitumor agents

Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity

Natural product evodiamine is a multitargeting antitumor lead compound. However, clinical development of evodiamine derivatives was hampered by poor water solubility and limited in vivo antitumor potency. Herein, a series of evodiamine–glucose conjugates were designed by additional targeting glucose transporter-1 (GLUT1). Compared with the lead compound, conjugate 8 exhibited obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also led to lower cytotoxicity to normal cells. Antitumor mechanism studies manifested that conjugate 8 acted by Top1/Top2 dual inhibition, apoptosis induction, and G2/M cell cycle arrest, which selectively targeted tumor cells with a high expression level of GLUT1. Thus, evodiamine–glucose conjugates showed promising features as potential antitumor agents