Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors

Based on reported pharmacophores as topoisomerase inhibitors, 2,5-dimethylthiophene/furan based N-acetyl pyrazolines were designed and envisaged as topoisomerase inhibitors. The target compounds were synthesized and tested in vitro against human topoisomerases in decatenation, relaxation, cleavage complex and DNA intercalation assays. Out of 29 compounds, three (10, 11 and 29) showed potent and selective topoisomerase II inhibitory activity with no intercalation with DNA. Further, molecular docking studies also endorsed them as ATP dependent topoisomerase II catalytic inhibitors. These compounds exerted potential anticancer effects on breast, colon, lung and prostate cancer cell lines at a low micromolar level, as compared to etoposide, and low toxicity to normal cells. Apart from the topoisomerase II inhibition, these compounds also induced a reactive oxygen species (ROS) level in cancer cells. The cell cycle analyses showed their apoptotic effect at the G1 phase.

Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors

Darpan,^ab   Gaurav Joshi,^a   Suyog M. Amrutkar,^c  Ashish T. Baviskar,^c   Harveen Kler,^a   Sandeep Singh,^d  Uttam C. Banerjee^c and   Raj Kumar*^ab  

Hide Affiliations

*

Corresponding authors

^a

Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
E-mail: raj.khunger@gmail.com, rajcps@cup.ac.in
Fax: +91-1636-236564
Tel: +91-0164-2864215

^b

Indo-Soviet Friendship College of Pharmacy, Moga, India

^c

Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Mohali, S. A. S. Nagar, Sec 67, India

^d

Centre for Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India

RSC Adv., 2016,6, 14880-14892

DOI: 10.1039/C5RA25705K

Scheme 1 Reagents and conditions: (a) 5% NaOH, ethanol, rt, 4–5 h, 65–82% (b) NH2NH2·H2O, CH3COOH, reflux, 4–6 h, 75–90%.






//////////

(2R,3S)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3] oxaphosphole 3- oxide

An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.

(2R,3S)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3] oxaphosphole 3- oxide

(2R,3S)-3-(tert-butyl)-2-(pyridin-2-yl)-2H-benzo[d][1,3] oxaphosphole 3- oxide: white solid,

mp 164.0-166.0 °C; [α]D 20 = + 87.4 (c 0.05, EtOH);

1 H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 5.0 Hz, 1H), 7.67 (qd, J = 7.0, 1.4 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.21   (m, 1H), 7.12 (m, 2H), 5.74 (d, J = 1.8 Hz, 1H), 1.37 (d, J = 5.0 Hz, 9H);

13C NMR (125 MHz, CDCl3): δ 163.9 (d, JC−P = 17.5 Hz), 154.3 (d, JC−P = 4.0 Hz), 149.3 (d, JC−P = 1.5 Hz),136.7 (d, JC−P = 1.8 Hz), 135.1 (d, JC−P = 1.9 Hz), 130.0 (d, JC−P = 6.1 Hz), 122.9 (d, JC−P = 2.0 Hz), 122.5 (d, JC−P = 9.0 Hz), 121.4 (d, JC−P = 2.6 Hz), 113.8 (d, JC−P = 90.9 Hz), 113.7 (d, JC−P = 5.6 Hz), 77.7 (d, JC−P = 53.9 Hz), 33.9 (d, JC−P = 71.7 Hz), 24.1;

 31P NMR (202 MHz, CDCl3): δ 60.5;

HRMS (ESI) [M+H]+ m/z calcd for [C16H19NO2P]+ is 288.1075, found 288.1148.

Synthesis of Enantioenriched 2-Alkyl Piperidine Derivatives through Asymmetric Reduction of Pyridinium Salts

Bo Qu*, Hari P. R. Mangunuru, Xudong Wei, Keith R. Fandrick, Jean-Nicolas Desrosiers, Joshua D. Sieber, Dmitry Kurouski, Nizar Haddad, Lalith P. Samankumara, Heewon Lee, Jolaine Savoie, Shengli Ma, Nelu Grinberg, Max Sarvestani, Nathan K. Yee, Jinhua J. Song, and Chris H. Senanayake

Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, United States

Org. Lett., Article ASAP

DOI: 10.1021/acs.orglett.6b02401

*E-mail: bo.qu@boehringer-ingelheim.com.

//////////////

Gabapentin Lactam (2-Aza-spiro[4,5]decan-3-one)

2-Azaspiro[4.5]decan-3-one

• Molecular FormulaC₉H₁₅NO
• Average mass153.221 

1-(Aminomethyl)cyclohexaneacetic acid lactam

2-Azaspiro[4.5]decan-3-on 

4,4-Pentamethylene-2-pyrrolidone

64744-50-9 [RN]

Melting point: 89–90 °C (reported: 90–91 °C);
Nagarajan, K.; Sivaramakrishnan, H.; Arulselvan, M. U.S. Patent US 7632953 B2, 2009.
Padaonkar, G.; Thennati, R. Indian Patent IN 186285, 2000.

.

1H NMR

  1H NMR (CDCl3, 300 MHz): δ 6.05 (bs, 1H, −NH), 3.15 (s, 2H, −CH2–NH−), 2.18 (s, 2H, −CH2CO−), 1.67–1.31 (unresolved m, 10H, cyclohexyl group), 

13C NMR (CDCl3, 75 MHz), δ 178.4 (−NHCO−), 53.8 (−CH2NH), 43.3 (−CH2CO−), 39.2, 36.7, 25.6, 22.8 (cyclohexyl group).

13C NMR


Gabapentin Lactam (2-Aza-spiro[4,5]decan-3-one)

MASS

13C NMR

1HNMR

IR

///////////





 Plitvice Lakes national park, Croatia, 



Map of Plitvice Lakes National Park
Plitvice Lakes National Park  

National park in Croatia
Plitviče Lakes National Park is a 295-sq.-km forest reserve in central Croatia. It's known for a chain of 16 terraced lakes, joined by waterfalls, that extend into a limestone canyon. Walkways and hiking trails wind around and across the water, and a Lake Kozjak ferry links the upper and lower lakes. The latter are the site of Veliki Slap, a 78m-high waterfall.
Address: Croatia

Plitvice Lakes National Park, Croatia

It's almost two hours (135 km / 83 miles) by bus fromZagreb to Plitvice Lakes National Park. Founded in 1949, it is the largest national park in Croatia and the oldest in Southeast Europe.

It is about 297 sq km (+73,000 acres) and in 1979 it was listed as a UNESCO World Heritage Site. The park is open all year round and receives over 900,000 visitors annually.


Plitvice is absolutely stunning!! There are 16 lakes (12 upper lakes and 4 lower lakes) that interconnect through a series of waterfalls, all surrounded by heavy woods and mountains. It is a great place to go for a hike and lose one's self in the scenery.

The water is so clear that you can see the fish swimming. Depending on the minerals in the water and the angle of the sun, the water's color ranges from azure blue to green.

To date, 1,267 different types of plants have been cataloged in the park.

There are different paths you can take to cover the park. I elected to go for trail "H" which is the 4 - 6 hour path. From the entrance I rode the shuttle train to the upper lakes area. I hiked down to where a shuttle boat dropped me off on the other side of the main lake. Then I hiked through the lower lakes canyon and up by the great waterfall. Then it was up along the east side of the canyon until I made it back to the starting point. 






I did it in about 3.5 hours. I should have taken the 8 hour path but I didn't want to take a chance on missing the last bus back to Zagreb. 


Oh well, there is always next time. I wonder how much of the lakes freeze? I would love to see the park in the winter with all of the snow and ice.

Finally today, we got out to Plitvice Lakes National Park.  It was about a 2 hour drive from Miloš’ home town of Crikvenica.  We were joined by his mom for a nice half-day trip on this lovely sunny warm day.

Since it’s still the off-season, only the Lower Lakes section of the park was open.  (But an added bonus was that there was a reduced rate to get into the park – half price – 55 kuna.)

Here’s a map and link for the park, if you want to get some more info:

Plitvice Official Website

(The map covers the entire region, just to put things into perspective.  You can see our driving route highlighted in blue.  Italy is on the left, across the Adriatic Sea.  In the middle of the photo is the Istrian Peninsula, which is part of Croatia.  Slovenia is to the north.  And to the right of Croatia, past Plitvice, is Bosnia.)

Northern Adriatic Region

We started out on our journey around 11:40am.  We had two big mountains to cross – twisty roads up and then twisty roads down.  We drove through some small towns and lots of countrysides.  When we got farther into the inland part of Croatia, you could see skeletons of old country houses that were still sitting damaged from the war in the early 1990s.

Even though the day was so warm, you could see snow up on one of the distant mountains.

Here are some pics from our drive…

Here’s a map of the actual park itself…

Plitvice Park Map

We arrived at the park around 1:45pm and set out on the trail.  Upon arriving from Entrance Number 1 (top of the park map), you are presented with the view of the Great Falls and the crystal clear waters below – particularly one of the most famous views featured in many travel photos.

View from the top

Taking the trail down the hillside gives you breathtaking sights of not only the falls, but also the various sections of the first of the lower lakes.  Then at the bottom are all these super cool wooden walkways over and along the water.

And throughout it all – are lots and lots of waterfalls.  There are so many fabulous views.  All I could think of over and over was just how awesome it was.  AWESOME!  And all those waterfalls every where just give you this amazing hit of energy.  Water rushing everywhere.  We hiked along the trail for awhile, then got on the boat that took us down the lake a little further.  From there, you can catch another boat that takes you to the opposite shore for more exploration.  From that point, you can access the upper lakes.  However, we couldn’t access that part of the park this time of year, nor did we have time, as the last boat to the other side was at 4:30pm.

I’ve heard that the summer season is super busy – lots of crowds.  But even today being mid-March, there were a decent amount of people there.

But here, let me stop talking and just show you.  We took over 440 photos, so it was hard to decide on the best ones, but here are some of the highlights:

Miloš at Plitvice

Jen and Miloš posing in front of the Great Falls

View from the trail descending the hillside

When we came around the corner to this spot, it truly looked like a fairy land!

Posing in the mist of the falls.

Pathway over the falls…

Look at the brilliant color of the water!

Miloš and his mom walking up the trail

One more pic before heading out of the park

//////////