Oleanolic-bioenhancer coloaded chitosan modified nanocarriers attenuate breast cancer cells by multimode mechanism and preserve female fertility.

Addressing multidrug resistant stage of breast cancer is an impediment for chemotherapy. Moreover, breast cancer chemotherapy has potential enduring confrontations i.e. related toxicity including effect on fertility of young female patients. The co-delivery of polyphenolic bio-enhancers with oleanolic acid in chitosan coated PLGA nanoparticles was designed for oral delivery with enhanced antitumor effect consecutively preserving the female fertility. The optimized oleanolic- bio-enhancer nano formulation CH-OA-B-PLGA with particle size was 342.2±3.7nm and zeta potential of 34.2±3.1mV was capable of lowering viability in MDAMB 231 cell line 16 times than OA. Further, mechanistic studies in MDAMB-231 cells revealed that CH-OA-PLGA induces apoptosis by mitochondrial membrane disruption; follows ROS mediated and caspase dependent apoptosis. The antitumor effect studied in 4-T1 induced Balb/c mice mammary tumor model displayed augmented antitumor potency by CH-OA-B-PLGA in comparison to OA. In the in vivo toxicity on Sprague-Dawley rat model, CH-OA-B-PLGA significantly displayed the safe profile and also preserves fertility in female rats. The experiment result suggests co-delivery of oleanolic acid with bio-enhancers as a breakthrough for developing safe chemotherapy for hormone independent breast cancer therapy countering the toxicity issues.

Design and synthesis of γ-butyrolactone derivatives as potential spermicidal agents.

A series of γ-butyrolactone derivatives has been designed and synthesized from commercially available 2-acetyl butyrolactone (3-acetyldihydrofuran-2(3H)-one, 1) by aminoalkylating its active methylene followed by condensation with different aldehydes. Compounds having amino group were further converted to their respective tartrate salts and were evaluated for spermicidal activity against human sperm in vitro. Compounds showing appreciable spermicidal activity at ⩽0.5% [3c, 4d (0.5%); 2c, 3d (0.1%); 2d, 4c (0.05%)] were tested for safety studies against human cervical (HeLa) cell line. These compounds were found safer than, Nonoxynol-9. One of the two most active compounds was also found to be the safest (IC50=961 µg/ml; 4c), while the second compound exhibited lower safety against HeLa (IC50=269 µg/ml; 2d). The compound 4c significantly reduced the number of free thiols on human sperm. All the compounds were inactive against Trichomonas vaginalis.

A unique dithiocarbamate chemistry during design & synthesis of novel sperm-immobilizing agents.

1-Substituted piperazinecarbodithioates were obtained by an unusual removal of CS2 in benzyl substituted dithiocarbamate derivatives under acid and basic conditions during design and synthesis of 1,4-(disubstituted)piperazinedicarbodithioates as double edged spermicides. A plausible mechanism for CS2 removal has been proposed. All synthesized compounds were subjected to spermicidal, antitrichomonal and antifungal activities. Twenty-one compounds irreversibly immobilized 100% sperm (MEC, 0.06-31.6 mM) while seven compounds exhibited multiple activities. Benzyl 4-(2-(piperidin-1-yl)ethyl) piperazine-1-(carbodithioate) (18) and 1-benzyl 4-(2-(piperidin-1-yl)ethyl)piperazine-1,4-bis(carbodithioate) (24) exhibited appreciable spermicidal (MEC, 0.07 and 0.06 mM), antifungal (MIC, 0.069-0.14 and >0.11 mM) and antitrichomonal (MIC, 1.38 and 0.14 mM) activities. The probable mode of action of these compounds seems to be through sulfhydryl binding which was confirmed by fluorescence labeling of sperm thiols.

Synthesis of 3-(1-alkyl/aminoalkyl-3-vinyl-piperidin-4-yl)-1-(quinolin-4-yl)-propan-1-ones and their 2-methylene derivatives as potential spermicidal and microbicidal agents.

A series of twenty two derivatives of 3-(1-alkyl/aminoalkyl-3-vinyl-piperidin-4-yl)-1-(quinolin-4-yl)-propan-1-one and their 2-methylene derivatives were synthesized from naturally abundant cinchonine (I). Tartarate salts of these compounds were prepared and evaluated for spermicidal activity. The most active compounds (24, 27, 34, 36, and 38) showing potent spermicidal activity were further evaluated against different strains of Trichomonas vaginalis, for antimicrobial activity, in HeLa cell lines for cytotoxicity and against Lactobacillus jensenii for eco-safety. The tartarate of 3-(1-pentyl-3-vinyl-piperidin-4-yl)-1-(quinolin-4-yl)-propan-1-one (27) was found to be more active than N-9 in spermicidal activity.

Synthesis of disulfide esters of dialkylaminocarbothioic acid as potent, non-detergent spermicidal agents.

S,S'-[disulfanediylbis(dialkylaminopropane-2,1-diyl)]bis- (dialkylaminothiocarbamate) (14-31) were prepared and evaluated for the spermicidal activity and antifungal activity. Dialkyldithiocarbamates (1-5) were reacted with epichlorohydrin to give 1-dialkylaminocarbothioic acid S-[(2,3-epithio)propyl]ester (7-11), these on further reaction with a secondary amine gave S,S'-[disulfanediylbis(dialkylaminopropane-2,1-diyl)]bis- (dialkylaminothiocarbamate) (14-31). Some of these compounds (16, 19-21, 23, 30, 31) were found to be very potent spermicidal agents with marginal antifungal activity. Two compounds (20, 21) were 25 times more active than nonoxynol-9 (N-9), the spermicide currently in the market.

Synthesis of benzenepropanamine analogues as non-detergent spermicides with antitrichomonas and anticandida activities.

Fifteen analogues of benzenepropanamine were synthesized and evaluated for their spermicidal as well as microbicidal activities against Trichomonas vaginalis and Candida spp. Several compounds showed appreciable dual activities. Compound 12 exhibited good spermicidal (MEC=0.1%) along with substantial anticandidal (MIC=0.05%) activities, while compounds 3 and 6 showed significant microbicidal activities with moderate spermicidal effect. The SAR of these structures is being discussed here in this communication. It is concluded that suitable structural modifications in this class of compounds at 3-amino position may lead to a potent spermicide with associated microbicidal activity.

The spermicidal and antitrichomonas activities of SSRI antidepressants.

The study investigated spermicidal and antitrichomonas activities of selective serotonin reuptake inhibitor (SSRI) antidepressants with a view to generate new lead for development of dual-function spermicidal microbicides, which is an urgent global need. Fluoxetine, Sertraline, and Fluvoxamine exhibited both spermicidal and anti-STI (antitrichomonas) activities in vitro, whereas Paroxetine and Citalopram showed only the spermicidal activity. Fluoxetine exhibited better activity profile than the other antidepressant drugs with its spermicidal and antitrichomonas activities being comparable to that of the OTC contraceptive Nonoxynol-9. The non-detergent nature of Fluoxetine and a much lower spermicidal ED50 value (than N-9) may add considerably to its merit as a candidate for microbicidal contraceptive. Thus, the antidepressants exhibiting both spermicidal and antitrichomonas activities might provide useful lead for the development of novel, dual-function spermicidal contraceptives.

Substituted acrylophenones and related mannich bases as possible spermicides and inhibitors of HIV envelope glycoprotein-CD4 interaction.

Several appropriately substituted 4-(dialkylamino-alkyl)-substituted-styryl-alkyl ketones or acetophenones were prepared and subjected to the Mannich reaction to yield compounds that would incorporate both alpha,beta-unsaturated keto groups and a substituted aminomethyl function with or without another olefinic moiety at position 4. The spermicidal activity of the prepared compounds was evaluated. Several compounds 2d, 4a and 4e were found to possess spermicidal activity at 0.005% concentration, while compounds 2a, 2c, 2f, 3a and 4b were active at 0.01% concentration. Compounds 2a, 2c, 3a, 4a and 4e also inhibited the interaction between recombinant HIV Env and CD4. Out of these, compound 2c was found to be most active.