A Democratic Developmental State in post-authoritarian Nigeria? Issues and prospects

This article, deploying data from documentary sources,examines issues in Nigeria’s democratization project and the prospect of a Democratic Developmental State (DDS) in post-authoritarian Nigeria. Drawing from the radical theory of the state, it notes that an autonomous state is pivotal to a successful DDS in the global South. In the light of this and based on the review of Nigeria’s development and democratization history, the article argues and concludes that, given the non-autonomous character of the Nigerian state and the politics that it engenders, the prospects of a DDS in Nigeria in the nearest future are rather slim

Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26±32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product

N-(3-Bromo-1,4-dioxo-1,4-dihydro-2-naphthyl)-4-fluoro-N-(4-fluorobenzoyl)benzamide

In the title compound, C24H12BrF2NO4, synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 4-fluorobenzoyl chloride, the two p-fluorophenyl rings are inclined at 73.9 (1) and 73.6 (1)° to the naphthoquinone ring system. The two imido carbonyl O atoms are anti to each other, while the fluorophenyl rings are located opposite each other, connected to the imide group in a funnel-like arrangement. This conformation allows the fluorine groups be oriented slightly away from each other. An examination of the packing shows a close intermolecular F...O contact of 2.982 (5) Å and a Br...O contact of 2.977 (4) Å. In addition, the molecules are linked by weak intermolecular C—H...O and C—H...F interactions

4-Hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1, 2-dihydroquinoline-3-carboxamide

The title compound, C20H17F3N 2O4, named tasquinimod, is a second-generation oral quinoline-3-carboxamide analogue, which is currently in phase III clinical trials for the treatment of metastatic prostate cancer. The quinoline unit is almost planar (r.m.s. deviation of fitted atoms = 0.0075 Å). The carboxamide side chain, substituted at position 3, is tilted by 88.07 (7)° to the quinoline plane. Both the methyl and carbonyl groups of this carboxamide side chain are in a syn conformation. The 4-(trifluoromethyl)phenyl plane is inclined at 50.62 (17)° to the plane of the carboxamide side chain, and at 87.14 (4)° to the plane of the quinoline ring system. The 4-hydroxy H atom acts as a double proton donor in an intramolecular hydrogen bond to the 5-position methoxy O atom and in an intermolecular contact to the 2-oxo group, generating a chain along [010] in the crystal structure

N-(3-Bromo-1,4-dioxo-1,4-dihydro-2-naphthyl)-2-chloro-N-(2-chlorobenzoyl)benzamide

The title compound, C24H12BrCl2NO4, was synthesized from 2-amino-3-bromo-1,4-naphthoquinone and 2-chlorobenzoyl chloride. The crystal structure shows that each of the chlorophenyl rings is inclined at about 60° to the naphthoquinone ring system. The two chlorophenyl rings adopt a conformation that ensures that chlorine substituents are anti so as to reduce electronic repulsion. An examination of the packing shows close O...Br and Cl...Cl contacts of 2.947 (2) and 3.346 (1) Å, respectively. In addition, the molecules are linked by weak intermolecular C—H...O and C—H...Cl interactions

Albumin-linked prostate-specific antigen-activated thapsigargin- and niclosamide-based molecular grenades targeting the microenvironment in metastatic castration-resistant prostate cancer

Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation. Unfortunately, once metastatic, no available therapy is curative. The vast majority will die despite aggressive systemic combinational androgen-ablation therapies. Thus, there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer (mCRPC). To accomplish this goal, advantage can be taken of the unique biology of mCRPC cells. Like their normal cell of origin, mCRPCs retain expression of the prostate-specific differentiation protein, prostate-specific antigen (PSA), which they abundantly secrete into their extracellular fluid (ECF). This unique, and essentially universal, secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as “molecular grenades” covalently linked to cysteine-34 of human serum albumin (HSA) via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis (i.e., “detonation”) releases the grenades restrictively within the ECF of mCRPC. This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days (i.e., pharmacokinetic effect) and increasing the tissue concentration of the maleimide coupled albumin delivery (MAD) in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites (i.e., enhanced permeability and retention effect). This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form. Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently “pull the pin” on the grenades releasing their lipophilic cell-penetrant toxins from HSA. Thus, if a sufficient level of “detonation” occurs, this will kill mCRPC cells, and sterilize the entire PSA-rich metastatic sites via a bystander effect. In this review, two examples of such MAD-PSA detonated molecular grenades are presented—one based upon thapsigagin and the other on niclosamide. Keywords: Albumin-linked prodrug, Maleimide coupled albumin delivery, Thapsigargin, Niclosamid

Design, Synthesis, and Evaluation of pH-Dependent Hydrolyzable Emetine Analogues as Treatment for Prostate Cancer

The N-2′ position of the natural product emetine has been derivatized to thiourea, urea, sulfonamide, dithiocarbamate, carbamate, and pH responsive hydrolyzable amide analogues. In vitro studies of these analogues in PC3 and LNCaP prostate cancer cell lines showed that the analogues are generally less cytotoxic (average IC₅₀ ranging from 0.079 to 10 μM) than emetine (IC₅₀ ranging from 0.0237 to 0.0329 μM). The pH sensitive sodium dithiocarbamate salt <b>13</b> and the amide analogues <b>21</b>, <b>22</b>, <b>26</b> (obtained from maleic and citraconic anhydrides) showed the most promise as acid-activatable prodrugs under mildly acidic conditions found in the cancer microenvironment. These prodrugs released 12–83% of emetine at pH 6.5 and 41–95% emetine at pH 5.5. Compounds <b>13</b> and <b>26</b> were further shown to exhibit increased cytotoxicity in PC3 cell culture medium that was already below pH 7.0 at the time of treatment